4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same

ABSTRACT

The present invention relates to benzoxazinones of formula I: ##STR1## or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.

This application claims the benefit of U.S. Provisional Application No. 60/027,137, filed Oct. 2, 1996, and U.S. Provisional Application No. 60/045,138, filed Apr. 30, 1997, and is a divisional of application Ser. No. 08/942,031, filed Oct. 1, 1997, now U.S. Pat. No. 5,874,430.

FIELD OF THE INVENTION

This invention relates generally to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones which are useful as inhibitors of HIV reverse transcriptase, pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as assay standards or reagents, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

Two distinct retroviruses, human immunodeficiency virus (HIV) type-1 (HIV-1) or type-2 (HIV-2), have been etiologically linked to the immunosuppressive disease, acquired immunodeficiency syndrome (AIDS). HIV seropositive individuals are initially asymptomatic but typically develop AIDS related complex (ARC) followed by AIDS. Affected individuals exhibit severe immunosuppression which predisposes them to debilitating and ultimately fatal opportunistic infections.

The disease AIDS is the end result of an HIV-1 or HIV-2 virus following its own complex life cycle. The virion life cycle begins with the virion attaching itself to the host human T-4 lymphocyte immune cell through the bonding of a glycoprotein on the surface of the virion's protective coat with the CD4 glycoprotein on the lymphocyte cell. Once attached, the virion sheds its glycoprotein coat, penetrates into the membrane of the host cell, and uncoats its RNA. The virion enzyme, reverse transcriptase, directs the process of transcribing the RNA into single-stranded DNA. The viral RNA is degraded and a second DNA strand is created. The now double-stranded DNA is integrated into the human cell's genes and those genes are used for virus reproduction.

At this point, RNA polymerase transcribes the integrated DNA into viral RNA. The viral RNA is translated into the precursor gag-pol fusion polyprotein. The polyprotein is then cleaved by the HIV protease enzyme to yield the mature viral proteins. Thus, HIV protease is responsible for regulating a cascade of cleavage events that lead to the virus particle's maturing into a virus that is capable of full infectivity.

The typical human immune system response, killing the invading virion, is taxed because the virus infects and kills the immune system's T cells. In addition, viral reverse transcriptase, the enzyme used in making a new virion particle, is not very specific, and causes transcription mistakes that result in continually changed glycoproteins on the surface of the viral protective coat. This lack of specificity decreases the immune system's effectiveness because antibodies specifically produced against one glycoprotein may be useless against another, hence reducing the number of antibodies available to fight the virus. The virus continues to reproduce while the immune response system continues to weaken. Eventually, the HIV largely holds free reign over the body's immune system, allowing opportunistic infections to set in and without the administration of antiviral agents, immunomodulators, or both, death may result.

There are at least three critical points in the virus's life cycle which have been identified as possible targets for antiviral drugs: (1) the initial attachment of the virion to the T-4 lymphocyte or macrophage site, (2) the transcription of viral RNA to viral DNA (reverse transcriptase, RT), and (3) the processing of gag-pol protein by HIV protease.

Inhibition of the virus at the second critical point, the viral RNA to viral DNA transcription process, has provided a number of the current therapies used in treading AIDS. This transcription must occur for the virion to reproduce because the virion's genes are encoded in RNA and the host cell reads only DNA. By introducing drugs that block the reverse transcriptase from completing the formation of viral DNA, HIV-1 replication can be stopped.

A number of compounds that interfere with viral replication have been developed to treat AIDS. For example, nucleoside analogs, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (ddC), 2',3'-dideoxythymidinene (d4T), 2',3'-dideoxyinosine (ddI), and 2',3'-dideoxy-3'-thiacytidine (3TC) have been shown to be relatively effective in halting HIV replication at the reverse transcriptase (RT) stage.

Non-nucleoside HIV reverse transcriptase inhibitors have also been discovered. As an example, it has been found that certain benzoxazinones are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and the treatment of AIDS. U.S. Pat. No. 5,519,021, the contents of which are hereby incorporated herein by reference, describe reverse transcriptase inhibitors which are benzoxazinones of the formula: ##STR2## wherein X is a halogen, Z may be O. However, benzoxazinones of this type are specifically excluded from the present invention.

In U.S. Pat. No. 5,519,021 one compound in particular, (-) 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI), shown below, ##STR3## has been found to be a potent and specific inhibitor of HIV-1 reverse transcriptase worthy of further study. NNRTI is described in Step D of Example 6 of the disclosure. Rat, monkey, and human microsomes treated with NNRTI, during investigation of the cytochrome P450 metabolism of NNRTI, produced a metabolite which was discovered to also be a potent inhibitor of HIV reverse transcriptase. This metabolite, its stereoisomer, stereoisomeric mixtures, and derivatives thereof are an embodiment of the present invention.

Even with the current success of reverse transcriptase inhibitors, it has been found that HIV patients can become resistant to a single inhibitor. Thus, it is desirable to develop additional inhibitors to further combat HIV infection.

SUMMARY OF THE INVENTION

Accordingly, one object of the present invention is to provide novel reverse transcriptase inhibitors.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a novel method for treating HIV infection which comprises administering to a host in need thereof a therapeutically effective combination of (a) one of the compounds of the present invention and (b) one or more compounds selected form the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

It is another object of the present invention to provide pharmaceutical compositions with reverse transcriptase inhibiting activity comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of the present invention.

It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of formula (I): ##STR4## wherein A, W, X, Y, Z, R¹ and R² are defined below, stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, are effective reverse transcriptase inhibitors.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[1] Thus, in a first embodiment, the present invention provides a novel compound of formula I: ##STR5## or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

also, provided that if X is CR⁴ and R⁴ is F, Cl, Br, or I, then:

(a) at least one of W, Y, and Z is other than CH;

(b) R² is --OCHR⁷ R⁸ or --NHCHR⁷ R⁸ ;

(c) if R² is --C.tbd.C--R⁸, then R⁸ is C₃₋₇ cycloalkyl substituted with 1 R⁹ ; or

(d) any combination of (a), (b), and (c);

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R² is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

provided that when R¹ is C₁₋₄ alkyl, then R² is --C.tbd.C--R⁸ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

[2] In a preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl; and,

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰.

[3] In a more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

R¹ is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃ ;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and,

p is selected from 1 and 2.

[4] In an even more preferred embodiment, the present invention provides a novel compound of formula I, wherein:

A is O;

R¹ is selected from CF₃, CF₂ H, C₂ F₅ ;

R² is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.

[5] In a further preferred embodiment, the compound of the present invention is selected from:

(+/-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Chloro-4-(2-(furan-2-yl)ethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one;

(+/-)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one; and,

(+/-)-4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

[6] In a second embodiment, the present invention provides a novel compound of formula II: ##STR6## or a salt or stereoisomer thereof, wherein: A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

p is selected from 0, 1, and 2.

[7] In a another preferred embodiment, the present invention provides a novel compound of formula II, wherein:

A is O; and,

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₃ alkyl, C₃₋₅ cycloalkyl.

[8] In a more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₂ H₅, isopropyl, cyclopropyl;

R³ is selected from H, F, Cl, Br, I, OCH₃, CH₃ ;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; and,

p is selected from 1 and 2.

[9] In an even more preferred embodiment, the present invention provides a novel compound of formula II, wherein:

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂.

[10] In a third embodiment, the present invention provides a novel process for making a compound of formula II: ##STR7## or a salt or stereoisomer thereof, comprising: (a) contacting a compound of formula III: ##STR8## or a suitable salt form thereof, with a carbonyl or thiocarbonyl delivering agent in the presence of a suitable solvent, wherein:

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

[11] In another preferred embodiment, in formulae II and III,

A is O;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

[12] In another more preferred embodiment, the carbonyl delivering agent is selected from phosgene, carbonyldiimidazole, chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate.

[13] In another even more preferred embodiment, the carbonyl delivering agent is phosgene and the solvent is toluene.

[14] In another more preferred embodiment, in step (a) a base is present and is selected from trimethylamine, triethylamine, and N,N-disopropylethylamine.

[15] In a fourth embodiment, the present invention provides of process for making a compound of formula Ia: ##STR9## or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:

(a) contacting a nucleophile, R^(2b), with a compound of formula II: ##STR10## or stereoisomer thereof in a suitable solvent, wherein: R^(2b) is selected from R⁸ R⁷ CH--OH, R⁸ R⁷ CH--OM, R⁸ R⁷ CHNH₂, R⁸ R⁷ CHNH--M, R⁸ --C.tbd.C--M, R⁷ R⁸ C═CH--M, R⁸ R⁷ CH(CH₂)_(p) --M, R⁸ CH═CHC(H) (R⁷)--M, R⁸ R⁷ CHCH═CH--M;

M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B;

A is O or S;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl;

R^(2a) is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

Q is selected from O, S and NH; and,

p is selected from 0, 1, and 2.

[16] In another preferred embodiment, in formulae Ia and II,

A is O;

R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ;

R^(2a) is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C═CR⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ;

R⁹ is selected from D, OH, OCH₃, CH₃, and F;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

[17] In another more preferred embodiment, in step (a), the compound of formula II is added to a solution containing the nucleophile.

[18] In another more preferred embodiment, in step (a), R^(2b) is R⁸ --C.tbd.C--M; and M is selected from Li, Mg, and Zn.

[19] In another even more preferred embodiment, in step (a), R⁸ --C.tbd.C--M is formed in situ by addition of a strong base to a solution containing R⁸ --C.tbd.C--H.

[20] In another further preferred embodiment, in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.

[21] In another further preferred embodiment, the compound of formula Ia is: ##STR11## the compound of formula Ia is: ##STR12## the nucleophile R^(2b) is lithium cyclopropylacetylide; and, the solvent is THF.

[22] In a fifth embodiment, the present invention provides a novel method of making a compound of formula IIIb: ##STR13## or stereoisomer or salt form thereof, comprising: (a) contacting a compound of formula IIIa: ##STR14## with R^(1a) -TMS and an anion, wherein: the anion is a fluoride or oxyanion and is selected from tetrabutylammonium fluoride, sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride, potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate;

Pg is an amine protecting group;

W is N or CR³ ;

X is N or CR⁴ ;

Y is N or CR⁵ ;

Z is N or CR⁶ ;

provided that if two of W, X, Y, and Z are N, then the remaining are other than N;

R^(1a) is selected from CF₃, CF₃ CF₂, and CF₃ CF₂ CF₂ ;

R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ;

alternatively, R³ and R⁴ together form --OCH₂ O--;

R⁵ is selected from H, F, Cl, Br, and I;

alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring;

R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ;

R⁷ is selected from H and C₁₋₃ alkyl;

R^(7a) is selected from H and C₁₋₃ alkyl;

R^(7b) is C₁₋₃ alkyl;

R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ;

p is selected from 0, 1, and 2.

[23] In another preferred embodiment, in formulae IIIa and IIIb,

the R^(1a) -TMS is trifluoromethyl trimethylsilane;

the anion is tetrabutylammonium fluoride;

Pg is trityl;

R^(1a) is CF₃ ;

R³ is selected from H, F, Cl, Br, I;

R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;

alternatively, R³ and R⁴ together form --OCH₂ O--; and,

R⁵ is selected from H, F;

R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ;

R⁷ is selected from H and CH₃ ;

R^(7a) is selected from H and CH₃ ;

R^(7b) is CH₃ ;

R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ;

R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and,

p is selected from 1 and 2.

[24] In another more preferred embodiment, the process further comprises:

(b) contacting a compound of formula IIIb with an oxidizing agent to form compound of formula IIIc: ##STR15##

[25] In another even more preferred embodiment, the oxidizing agent is MnO₂.

In a fifth embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a sixth embodiment, the present invention provides a novel method for treating HIV infection which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of formula I or pharmaceutically acceptable salt form thereof.

In a seventh embodiment, the p resent invention provides a novel method of treating HIV infection which comprises administering, in combination, to a host in need thereof a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors.

In another preferred embodiment, the reverse transcriptase inhibitor is a nucleoside reverse transcriptase inhibitor.

In another more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, 3TC, rescriptor, ddI, ddC, and d4T and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, VX-478, nelfinavir, KNI-272, CGP-61755, and U-103017.

In an even more preferred embodiment, the nucleoside reverse transcriptase inhibitor is selected from AZT, rescriptor, and 3TC and the protease inhibitor is selected from saquinavir, ritonavir, indinavir, and nelfinavir.

In a still further preferred embodiment, the nucleoside reverse transcriptase inhibitor is AZT.

In another still further preferred embodiment, the protease inhibitor is indinavir.

In a eighth embodiment, the present invention provides a pharmaceutical kit useful for the treatment of HIV infection, which comprises a therapeutically effective amount of:

(a) a compound of formula I; and,

(b) at least one compound selected from the group consisting of HIV reverse transcriptase inhibitors and HIV protease inhibitors, in one or more sterile containers.

In a ninth embodiment, the present invention provides a novel method of inhibiting HIV present in a body fluid sample which comprises treating the body fluid sample with an effective amount of a compound of formula I.

In a tenth embodiment, the present invention to provides a novel a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV reverse transcriptase, HIV growth, or both.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.

The reactions of the synthetic methods claimed herein may be, as noted herein, carried out in the presence of a suitable base, said suitable base being any of a variety of bases, the presence of which in the reaction facilitates the synthesis of the desired product. Suitable bases may be selected by one of skill in the art of organic synthesis. Suitable bases include, but are not intended to be limited to, inorganic bases such as alkali metal, alkali earth metal, thallium, and ammonium hydroxides, alkoxides, phosphates, and carbonates, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, thallium hydroxide, thallium carbonate, tetra-n-butylammonium carbonate, and ammonium hydroxide. Suitable bases also include organic bases, including but not limited to aromatic and aliphatic amines, such as pyridine; trialkyl amines such as triethylamine, N,N-diisopropylethylamine, N,N-diethylcyclohexylamine, N,N-dimethylcyclohexylamine, N,N,N'-triethylenediamine, N,N-dimethyloctylamine; 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); 1,4-diazabicyclo[2.2.2]octane (DABCO); 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); tetramethylethylenediamine (TMEDA); and substituted pyridines such as N,N-dimethylaminopyridine (DMAP), 4-pyrrolidinopyridine, 4-piperidinopyridine.

Suitable halogenated solvents include: carbon tetrachloride, bromodichloromethane, dibromochloromethane, bromoform, chloroform, bromochloromethane, dibromomethane, butyl chloride, dichloromethane, tetrachloroethylene, trichloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane, 2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene, o-dichlorobenzene, chlorobenzene, or fluorobenzene.

Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.

Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, anisole, benzyl alcohol, phenol, or glycerol.

Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethyl sulfoxide, propionitrile, ethyl formate, methyl acetate, hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate, sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

As used herein, the term "amine protecting group" (or "N-protected") refers to any group known in the art of organic synthesis for the protection of amine groups. As used herein, the term "amine protecting group reagent" refers to any reagent known in the art of organic synthesis for the protection of amine groups which may be reacted with an amine to provide an amine protected with an amine protecting group. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl (trityl) and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

Amine protecting groups may include, but are not limited to the following: 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothio-xanthyl)]methyloxycarbonyl; 2-trimethylsilylethyloxycarbonyl; 2-phenylethyloxycarbonyl; 1,1-dimethyl-2,2-dibromoethyloxycarbonyl; 1-methyl-1-(4-biphenylyl)ethyloxycarbonyl; benzyloxycarbonyl; p-nitrobenzyloxycarbonyl; 2-(p-toluenesulfonyl)ethyloxycarbonyl; m-chloro-p-acyloxybenzyloxycarbonyl, 5-benzyisoxazolylmethyloxycarbonyl; p-(dihydroxyboryl)benzyloxycarbonyl; m-nitrophenyloxycarbonyl; o-nitrobenzyloxycarbonyl; 3,5-dimethoxybenzyloxycarbonyl; 3,4-dimethoxy-6-nitrobenzyloxycarbonyl; N'-p-toluenesulfonylaminocarbonyl; t-amyloxycarbonyl; p-decyloxybenzyloxycarbonyl; diisopropylmethyloxycarbonyl; 2,2-dimethoxycarbonylvinyloxycarbonyl; di(2-pyridyl)methyloxycarbonyl; 2-furanylmethyloxycarbonyl; phthalimide; dithiasuccinimide; 2,5-dimethylpyrrole; benzyl; 5-dibenzylsuberyl; triphenylmethyl; benzylidene; diphenylmethylene; or methanesulfonamide.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --C_(v) F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. "Cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like. "Alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.

"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo. "Counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.

As used herein, "aryl" or "aromatic residue" is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as phenyl or naphthyl. As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term "heterocycle" or "heterocyclic system" is intended to mean a stable 5- to 6-membered monocyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term "aromatic heterocyclic system" is intended to mean a stable 5- to 6-membered monocyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 3 heteroatoms independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 2-pyrrolidonyl, 2H-pyrrolyl, 4-piperidonyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoxazolyl, morpholinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl., oxazolyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, tetrahydrofuranyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, and 1,3,4-triazolyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, and oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, "HIV reverse transcriptase inhibitor" is intended to refer to both nucleoside and non-nucleoside inhibitors of HIV reverse transcriptase (RT). Examples of nucleoside RT inhibitors include, but are not limited to, AZT, ddC, ddI, d4T, and 3TC. Examples of non-nucleoside RT inhibitors include, but are not limited to, rescriptor (delavirdine, Pharmacia and Upjohn), viviradine (Pharmacia and Upjohn U90152S), TIBO derivatives, BI-RG-587, nevirapine, L-697,661, LY 73497, and Ro 18,893 (Roche).

As used herein, "HIV protease inhibitor" is intended to refer to compounds which inhibit HIV protease. Examples include, but are not limited, saquinavir (Roche, Ro31-8959), ritonavir (Abbott, ABT-538), indinavir (Merck, MK-639), VX-478 (Vertex/Glaxo Wellcome), nelfinavir (Agouron, AG-1343), KNI-272 (Japan Energy), CGP-61755 (Ciba-Geigy), and U-103017 (Pharmacia and Upjohn). Additional examples include the cyclic protease inhibitors disclosed in WO93/07128, WO 94/19329, WO 94/22840, and PCT Application Number US96/03426.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

"Prodrugs" are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) or other formulas or compounds of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the present invention, for example formula (I), are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein the hydroxy or amino group is bonded to any group that, when the prodrug is administered to a mammalian subject, cleaves to form a free hydroxyl or free amino, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention, and the like.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated by the present invention.

"Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.

"Therapeutically effective amount" is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit HIV infection or treat the symptoms of HIV infection in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of HIV replication) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased antiviral effect, or some other beneficial effect of the combination compared with the individual components.

SYNTHESIS

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Each of the references cited below are hereby incorporated herein by reference. ##STR16##

Scheme 1 illustrates a method of making 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted 2-aminobenzoic acid. The acid is converted to its N-methoxy-N-methyl amide derivative which can then be displaced to obtain the R¹ -substituted ketone. Subsequent addition of another metallic species provides the alcohol which is readily cyclized with phosgene or an equivalent thereof. ##STR17##

Scheme 2 describes a means of obtaining 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones starting from an appropriately substituted aniline. After iodination, the trifluoromethyl group can be introduced using a strong base and ethyl trifluoroacetate. The second 4-substituent can then be added through anion attack on the ketone or using other means well known to those of skill in the art. Cyclization can be then be completed as in Scheme 1. ##STR18##

Because certain benzo-substituents are incompatible with the methods of Schemes 1 and 2, it may be necessary to protect these groups before forming the benzoxazinone. In Scheme 3 there is shown a means of obtaining carbonyl-substituted 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones. After iodination of an acetyl-aniline, the acetyl group is protected by means well known to those of skill in the art, such as using 1,3-propanedithiol. The same procedures as in Scheme 2 are used to arrive at the cyclized product. Deprotection of the ketone can then be achieved using HgCl₂ and HgO or other means well known to those of skill in the art. ##STR19##

A method for forming 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones, wherein R² is a vinyl or alkynyl group, is described in Scheme 4. Starting from an appropriately substituted ketone which can be obtained using the procedure of Scheme 1 or 2, an acetylide is added. The product can be deprotected and cyclized to obtain the alkynyl-substituted material. Alternatively, the vinyl compounds can be obtained by reduction of the alkyne with a reducing agent, such as LiAlH₄, deprotection by standard means, and cyclization. ##STR20##

Scheme 5 describes an alternate route to 4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from anilines, wherein the aniline is protected, ester addition is accomplished using a strong base and the amine protecting group is removed. The R² group can then be added, e.g. via an acetylide, followed by cyclization. ##STR21##

An intermediate useful in the preparation of the presently claimed compounds is 2-trifluoroacetylaniline. The starting 4-chloro-2-trifluoroacetylaniline can be made as shown in Scheme 2. Reduction and reoxidation removes the chloro group leaving the desired intermediate. ##STR22##

Scheme 7A describes a novel method of making 2-trifluoroacetylanilines as well as how these compounds can be further modified to make the presently claimed compounds. The protected aldehyde can be made from the N-methoxy-N-methyl amide of Scheme 1, by addition of a protecting group, preferably trityl, and reduction of the amide to the aldehyde. Other protecting groups known to those of skill in the art can be used in place of the shown trityl group. ##STR23##

Scheme 7B illustrates specific steps of Scheme 7A. Intermediate IIIb (R^(1a) is selected from CF₃, CF₃ CF₂, and CF₃ CF₂ CF₂) is useful for making some of the presently claimed compounds. Pg is an amine protecting group as defined previously, preferably trityl (triphenylmethyl). The protected or unprotected aminobenzaldehyde, preferably protected, is treated with a perfluoralkyl trimethylsilane, preferably trifluoromethyl trimethylsilane, followed by fluoride anion, preferably tetrabutylammonium fluoride. In the same fashion, CF₃ CF₂ TMS, CF₃ CF₂ CF₂ TMS can also be used to prepare the appropriately substituted ketones. Other sources of fluoride anion such as sodium fluoride, potassium fluoride, lithium fluoride, cesium fluoride as well as oxyanionic species such as potassium tert-butoxide, sodium methoxide, sodium ethoxide and sodium trimethylsilanolate can also be used. Aprotic solvents such as DMF and THF can be used, preferably THF. The amount of perfluoralkyl trimethylsilane used can be from about 1 to about 3 equivalents with an equivalent amount of fluoride anion or oxyanionic species. The reaction can be typically carried out at temperatures between about -20° C. to about 50° C., preferably about -10 to about 10° C., more preferably about 0° C.

Conversion of IIIb to IIIc can be achieved by using an oxidizing agent well known to one of skill in the art such as MnO₂, PDC, PCC, K₂ Cr₂ O₇, CrO₃, KMnO₄, BaMNO₄, Pb(OAc)₄, and RuO₄. A preferred oxidant is MnO₂. Such conversion can be performed in an aprotic solvent like THF, DMF, dichloromethane dichloroethane, or tetrachloroethane, preferably dichloromethane. ##STR24##

Scheme 8 illustrates a method of forming aza-4,4-disubstituted-1,4-dihydro-2H-3,1-benzoxazin-2-ones from an appropriately substituted amino-pyridine. Carbonyl addition to the pyridine can be accomplished using a strong base and an appropriate ketone. Addition of base can afford the cyclized product. ##STR25##

An additional means of making 4-alkynyl-1,4-dihydro-2H-3,1-benzoxazin-2-ones is shown in Scheme 9. The alkyne group is added to the keto-aniline via a Grignard type addition, followed by cyclization. The alkyne group of the product can then be modified to obtain the desired compound. ##STR26##

In addition to the methods of obtaining keto-anilines described in Schemes 1 and 2, nucleophilic opening of isatoic anhydrides can also be used as shown in Scheme 10. This reaction is accomplished by using an anionic nucleophile of the group R^(1a). See Mack et al, J. Heterocyclic Chem. 1987, 24, 1733-1739; Coppola et al, J. Org. Chem. 1976, 41(6), 825-831; Takimoto et al, Fukuoka Univ. Sci. Reports 1985, 15(1), 37-38; Kadin et al, Synthesis 1977, 500-501; Staiger et al, J. Org. Chem. 1959, 24, 1214-1219.

It is preferred that the stoichiometry of the isatoic anhydride reagent to nucleophile is about 1.0 to 2.1 molar equivalents. The use of 1.0 eq. or more (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0) of anion (or anion precursor) is preferred to force the conversion and improve the isolated yield. Preferably, the temperature used is from -20 to +35° C., with temperatures below 0° C. being more preferred and -20° C. being even more preferred. Reactions are run to about completion with time dependent upon inter alia nucleophile, solvent, and temperature. Preferably this nucleophilic addition is run in THF, but any aprotic solvent would be suitable. Reaction with the active nucleophilic anion is the only criterion for exclusion of a solvent. ##STR27##

An intermediate in this novel process is the chlorobenzoxazinone (II) which can be synthesized from the corresponding keto-aniline as shown in Scheme 11. The preparation of compounds of formula II works well with either the free base of the keto-aniline or its hydrochloride hydrate, though the free base is preferred due to its inherent reactivity. The carbonylation or thiocarbonylation reagent is selected from the group: phosgene (COCl₂), thiophosgene (CSCl₂), carbonyldiimidazole (CDI), chloromethylcarbonate, chloroethylcarbonate, dimethylcarbonate, diethylcarbonate, and di-t-butylcarbonate. Preferably, phosgene is used as the carbonylation reagent.

About 1, 2, 3, 4, or 5 equivalents of carbonylation or thiocarbonylation reagent are used, preferably from about 1 to about 2.5, even more preferably from about 1 to 2, and still further preferably about 1, 1.1, 1.2, 1.3, 1.4, or 1.5 equivalents. With volatile reagents like phosgene more than one equivalent can help the conversion and yield of the reaction but is not necessary to effect transformation.

Solvents such as toluene may be used. Additional non-reactive solvents, such as ethers (e.g., dimethyl ether and diethyl ether), hydrocarbons (e.g., hexane and cyclohexane) or other aromatic solvents (e.g., benzene, anisole, or quinoline) can also be used. Solvents with boiling points around that of toluene or higher are preferred. Use of such solvents allows heat to be applied to the reaction to promote the cyclization. When the preferred carbonylation reagent, phosgene is use, heat helps drive off the HCl generated and promote the closure reaction. When toluene is used, it is preferred to run the reaction near toluene's boiling point. However, one of ordinary skill in the art would recognize that too high of a temperature may decompose the product. In addition, too low of a temperature may cause an undesirably slow reaction. Reaction progress may be determined by the decoloration of the reaction mixture (indicating consumption of starting material) and confirmation of completeness by proton NMR. The reaction may be catalyzed by the addition of an acid scavenger such as an amine base (e.g., triethylamine or Hunigs base) or an inorganic base (e.g., sodium carbonate or potassium). ##STR28##

Scheme 12 describes routes to a variety of R² -substituted compounds of formula Ia by reacting a nucleophile (R^(2b)) with a compound of formula II (preferably R^(1a) is CF₃). This displacement reaction is quite versatile and a large range of nucleophiles can be used. Preferably the nucleophile is an amine (e.g., R⁸ R⁷ CHNH) or a metallic species selected from R⁸ R⁷ CH--OM, R⁸ R⁷ CH--SM, R⁸ R⁷ CHNH--M, R⁸ --C.tbd.C--M, R⁷ R⁷ C═CH--M, R⁸ R⁷ CH(CH₂)_(p) --M, R⁸ CH═CHC(H) (R⁷)--M, and R⁸ R⁷ CHCH═CH--M. In addition, R⁸ R⁷ CH--OH and its thiol analog, R⁸ R⁷ CH--SH, can be used without formation of their corresponding anions. The metallic moiety, M, is selected from the group Na, Li, Zn, Mg, Cu, Pd, Pt, Sn, Al, and B, preferably Li, Mg, or Zn.

If an metallic nucleophile is used, it may be made in situ by methods known to those of skill in the art or formed by methods known to those of skill in the art and then added to a solution. In either case, it is preferred that the compound of formula II is added to a solution containing the nucleophile.

Preferably, the nucleophile is an acetylide (i.e., R⁸ C.tbd.C--M) with Li, Mg, or Zn as the counterion. Acetylides are well known in the art. Preferably, R⁸ --C.tbd.C--M is formed in situ by addition of a strong base to a solution containing R⁸ --C.tbd.C--H. Strong bases are well known to those of skill in the art and include, but are not limited to n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium. Preferably, the strong base is n-butyl lithium. The acetylide may also be made in situ by addition of a strong base to a dihalo-olefin (e.g., Br₂ C═CHR⁸).

In the nucleophilic addition reactions the stochiometery is preferably about one equivalent of benzoxazinone to about 1.0 to 2.5 equivalents of nucleophile (e.g., 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, or 2.5). More preferable about 1.8 to 2.4 equivalents are used. Even more preferably, 2.1 equivalents of nucleophile are used. It is noted that less than one equivalent may be used, but care must be taken as N--H deprotonation reaction may compete with nucleophilic addition. It is preferable to run the additions from -40 to 0° C., more preferably about -20° C. The solvent used is preferably THF, but any aprotic solvent, such as dimethyl ether, diethyl ether, benzene, or toluene, should be suitable. Non-reaction with the nucleophile, specifically the nucleophilic anion, is the only criterion for exclusion of a solvent.

An additional example of the utility of the final nucleophilic addition step of the present invention is shown in Scheme 13. ##STR29##

A preferred example of the present process is shown in Scheme 14. ##STR30##

In Scheme 14, the preferred temperature of the carbonylation reaction is from about 104 to about 100° C. and the preferred temperature of the acetylide addition is about -20° C.

One enantiomer of a compound of Formula I may display superior activity compared with the other. Thus, both of the following stereochemistries are considered to be a part of the present invention. ##STR31## When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Andrew S. Thompson, et al, Tet. lett. 1995, 36, 8937-8940.

Another method of forming a compound wherein Z is C(OH) involves incubating NNRTI, or a derivative thereof, in microsomes obtained from male rats, male rhesus monkeys or humans, preferably male rats. In addition, it is preferable to orally dose the male rats with NNRTI prior to collection of their livers and microsomal isolation. This procedure will be described in the following Example section.

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: "° C. " for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "eq" for equivalent or equivalents, "g" for gram or grams, "mg" for milligram or milligrams, "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" for hour or hours, "m" for multiplet, "M" for molar, "min" for minute or minutes, "MHz" for megahertz, "MS" for mass spectroscopy, "nmr" or "NMR" for nuclear magnetic resonance spectroscopy, "t" for triplet, "TLC" for thin layer chromatography, "EDAC" for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, "DIPEA" for diisopropylethylamine, "TBAF" for tetrabutylammonium fluoride, "LAH" for lithium aluminium hydride, and "TEA" for triethylamine.

Example 1 ##STR32## Preparation of (+--)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4'-Chloro-2'-methoxy-2,2-dimethylpropionanilide

A stirred solution of 22.6 g (100 mmol) of stannous chloride dihydrate in 40 mL of absolute ethanol was heated to reflux and treated with 3.75 g (20 mmol) of 5-chloro-2-nitroanisole in 20 mL of 1:1 ethanol-tetrahydrofuran over 3 min. Stirring at reflux for an additional 10 minutes gave a clear solution which was then cooled to 0° C. The mixture was treated with aqueous Na₂ CO₃ until a pH of 8-9 was reached. The colloidal suspension was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated NaHCO₃ then brine. The solution was dried (MgSO₄) and concentrated under reduced pressure. The crude oil was dissolved in 40 mL of CH₂ Cl₂ and cooled to 0° C. The solution was treated with 4.2 mL (30 mmol) of triethylamine followed by 2.8 mL (23 mmol) of pivaloyl chloride. After stirring 2 h at 0° C. the mixture was quenched with 0.5 N HCl, and the phases were separated. The aqueous phase was extracted with 100 mL of 1:1 ether-hexanes, and the combined organic extracts were washed sequentially with 0.1 N HCl, dilute K₂ CO₃, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give 4.68 g (97%) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide as an tan solid, mp 66-69° C. ¹ H NMR (300 MHz, CDCl₃) δ 6 8.36(d, 1H, J=8.8 Hz); 8.03(br. s, 1H); 6.94(dd, 1H, J=8.8, 2.2 Hz); 6.86(d, 1H, J=2.2 Hz); 3.90(s, 3H); 1.32(s, 9H). High resolution mass spec: calculated for C₁₂ H₁₇ NO₂ Cl(M+H)⁺ : 242.0948, found: 242.0943. Analysis calculated for C₁₂ H₁₆ NO₂ Cl: C, 59.63; H, 6.67; N, 5.79; Cl, 14.67. Found: C, 59.73; H, 6.67; N, 5.57; Cl, 14.42.

Part B: Preparation of 2'-Amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (-20° C.) solution of 12.1 g (50 mmol) of 4'-chloro-2'-methoxy-2,2-dimethylpropionanilide in 150 mL of THF was added 87 mL (115 mmol) of 1.3 M s-BuLi in cyclohexane over 15 min. The dark solution was warmed to 0° C. and stirred for 1.2 h. The solution was re-cooled to -20° C. and treated with 14.3 mL (120 mmol) of ethyl trifluoroacetate over 5 min. The reaction was warmed to 0° C., stirred 15 min., and quenched with saturated aqueous NaHCO₃. The mixture was extracted with hexanes and then with ether, and the combined organic extracts were washed sequentially with 0.5 N HCl, water, and brine. The solution was dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude amide was dissolved in 20 mL of 1,2-dimethoxyethane and treated with 100 mL of 6 N aqueous HCl. The mixture was stirred at reflux for 2 h, cooled to 0° C., and brought to pH 9 with K₂ CO₃. The mixture was extracted twice with ether, and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give an oily solid. This crude product was recrystallized from hexanes and a minimal amount of ethyl acetate to give 7.75 g (61%) of 2'-amino-5'-chloro-3-methoxy-2,2,2-trifluoroacetophenone as yellow needles, mp 124.5-125.5° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.32-7.35(m, 1H); 6.87(br. s, 2H); 6.84(d, 1H, J=1.8 Hz); 3.92(s, 3H). High resolution mass spec: calculated for C₉ H₈ NO₂ ClF₃ (M+H)⁺ : 254.0196, found: 254.0194. Analysis calculated for C₉ H₇ NO₂ ClF₃ : C, 42.62; H, 2.78; N, 5.52; Cl, 13.98. Found: C, 42.52; H, 3.04; N, 5.40; Cl, 13.74.

Part C: Preparation of 2'-Amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 31.2 g (123 mmol) of 2'-amino-5'-chloro-3'-methoxy-2,2,2-trifluoroacetophenone in 150 mL of CH₂ Cl₂ was added 550 mL (550 mmol) of 1 M BBr₃ in CH₂ Cl₂ over 20 min. The dark solution was stirred 17 h at ambient temperature, re-cooled to 0° C., and fitted with a pressure-equalizing dropping addition funnel and a Claisen adapter connected by rubber tubing to a large water scrubber. The reaction was carefully quenched by dropwise addition of aqueous Na₂ CO₃ until a pH of 7-8 was reached. The phases were separated, and the aqueous phase was extracted with 1 liter of 1:1 ether-hexanes. The combined organic phases were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure to afford 30.1 g (100%) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone as a chalky brown solid, mp 120-122° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.33-7.36(m, 1H); 6.88(d, 1H, J=1.8 Hz); 6.75(br. s, 2H); 5.78(br. s, 1H). High resolution mass spec: calculated for C₈ H₆ NO₂ ClF₃ (M+H)⁺ : 240.0039, found: 240.0029.

Part D: Preparation of 2'-Amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone

To a stirred, cooled (0° C.) solution of 29.3 g (122 mmol) of 2'-amino-5'-chloro-3'-hydroxy-2,2,2-trifluoroacetophenone in 280 mL of DMF was added 23.8 g (350 mmol) of imidazole followed by 66 g (250 mmol) of t-butyldimethylsilyl trifluoromethanesulfonate over 10 min. The reaction was stirred 5 h at 0° C. and diluted with 800 mL of 1:1 ether-hexanes. The solution was washed twice with water and once with brine, dried (MgSO₄) and concentrated under reduced pressure to give a dark oil. The crude product was rapidly passed through an 800 g plug of silica gel (elution with hexanes followed by 6:1 hexanes-ether) to afford, after evaporation of solvent, 42.5 g (98%) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone as a yellow oil. The product solidified after extended evacuation at 0.01 torr to give a yellow solid, mp 45-46.5° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.34-7.36(m, 1H); 6.85(d, 1H, J=2.2 Hz); 6.7-6.8(br. s, 2H); 1.03(s, 9H); 0.30(s, 6H). High resolution mass spec: calculated for C₁₄ H₂₀ NO₂ ClF₃ Si(M+H)⁺ : 354.0904, found: 354.0900. Analysis calculated for C₁₄ H₁₉ NO₂ ClF₃ Si: C, 47.52; H, 5.41; N, 3.97; Cl, 10.02. Found: C, 47.71; H, 5.36; N, 3.87; Cl, 10.02.

Part E: Preparation of (+/-)-2-(2-Amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol

To a stirred, cooled (0° C.) solution of 31.8 mL (300 mmol) of 5-chloro-1-pentyne in 250 mL of THF was added 252 mL (630 mmol) of 2.5 M n-BuLi in hexanes over 20 min. Over the course of the addition the internal temperature had warmed to ambient temperature, and the mixture was stirred at this temperature for 40 min. The reaction was cooled to -20° C. and treated with a solution of 32.7 g (97.4 mmol) of 2'-amino-5'-chloro-3'-(t-butyldimethylsilyloxy)-2,2,2-trifluoroacetophenone in 50 mL of THF over 10 min. The dark solution was stirred an additional 30 min and the cold bath was removed. The reaction was stirred 5 min and poured into 800 mL of 0° C. 1 N citric acid with rapid stirring. The mixture was extracted twice with ether, and the combined organic extracts were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 28.8 g (70%) of (+/-)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an off-white solid, mp 125-126° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.22(d, ¹ H, J=2.2 Hz); 6.76(d, 1H, J=2.2 Hz); 4.86(br. s, 1H); 4.39(br. s, 2H); 1.32-1.43(m, 1H)102(s, 9H); 0.79-0.92(m, 4H)1; 0.27(s, 3H) 0.26(s, 3H). High resolution mass spec: calculated for C₁₉ H₂₆ NO₂ ClF₃ Si(M+H)⁺ : 420.1373, found: 420.1363.

Part F: Preparation of (+/-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (-25° C.) solution of 28.8 g(68.6 mmol) (+/-)-2-(2-amino-5-chloro-3-(t-butyldimethylsilyloxy)phenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 600 mL of toluene was added 36 mL (206 mmol) of N, N-diisopropylethylamine followed by 38.9 mL (75 mmol) of a 1.93 M solution of phosgene in toluene over 20 min. The solution was stirred an additional 20 min. at -25° C. after which time it was warmed to -5° C. and quenched with water. The mixture was washed with 100 mL of 1 N aqueous HCl then brine, dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was dissolved in 200 mL of THF, cooled to 0° C., and treated with 40 mL of 1 M tetra-(n-butyl)ammonium fluoride in THF over 5 min. The solution was diluted with 200 mL of ether and washed sequentially with 1 M aqueous citric acid, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel. Elution with 1:3 ether-hexanes then 1:1 ether-hexanes afforded, after concentration under reduced pressure, 21.4 g (94%) of (+/-)-6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹ H NMR (300 MHz, CDCl₃) δ 8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). High resolution mass spec: calculated for C₁₄ H₁₀ NO₃ ClF₃ (M+H)⁺ : 332.0301, found: 332.0283.

Example 2 ##STR33## Preparation of (-)-6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Chromatography of 22 g of racemic 6-chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (I) on a Chiralpak AD-7.5 cm I.D.×30 gm column using 20% methanol-80% carbon dioxide as the mobile phase at a flow rate of 120 mL/min. gave two fractions. The faster-eluting fraction was concentrated and recrystallized from hexanes and a minimal amount of ethyl acetate to afford 5 g of the title compound as a white solid, mp 170-172° C. ¹ H NMR (300 MHz, CDCl₃) δ 8.46(br s, 1H); 7.01-7.07(m, 2H); 1.33-1.43(m, 1H); 0.81-0.97(m, 4H). [α]Na_(d) (25° C.)=-32°, c=0.28. Analysis calculated for C₁₄ H₉ NO₃ ClF₃ : C, 50.70; H, 2.75; N, 4.22; Cl, 10.69. Found: C, 50.74; H, 2.86; N, 4.26; Cl, 10.77.

Example 3 Preparation of (-) 6-Chloro-4-(cyclopropylethynyl)-8-hydroxy-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one by Rat Hepatic Microsomal Fractions

Incubation of (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (NNRTI) with hepatic microsomes from rats previously treated with NNRTI and cofactors required to support cytochromes P450 oxidative metabolism resulted in the formation of one major metabolite separable from NNRTI by reverse phase high performance liquid chromatography (HPLC). Incubations were conducted for 2 hours at 37° C. in a physiological buffer. After precipitating the protein with acetonitrile, the supernatants were dried under nitrogen and reconstituted in a mixture of 55:45 (v/v) acetonitrile:0.01% aqueous formic acid (pH 3.5) and injected onto the HPLC system. The column effluent was monitored at 247 nm. The single peak observed to elute at approximately 4 minutes was collected and combined from multiple injections. Final purification was accomplished using the same HPLC system and a linear gradient developed over 15 minutes starting with solvent A (50:50 (v/v) methanol:0.01% aqueous formic acid, pH 3.5) and increasing the proportion of solvent B (80:20 v/v methanol:0.01% aqueous formic acid pH 3.5), then holding solvent B constant for 5 minutes before re-equilibration with solvent A. The single, sharp peak eluting at approximately 16.5 minutes was collected and dried under vacuum.

The purified metabolite described above was dissolved in 0.2 mL of methanol-d4 and placed in a 3 mm NMR tube. The proton NMR spectrum was acquired using a 30 degree pulse, a 4 second acquisition time and a 2 second relaxation delay during which the residual water signal was suppressed by selective irradiation. The spectrum was referenced to solvent at 3.30 ppm.

Example 4 ##STR34## Preparation of (+/-)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4'-Chloro-2'-fluoro-2,2-dimethylpropionanilide

To a stirred, cooled (0° C.) solution of 3.64 g (25.0 mmol) of 4-chloro-2-fluoroaniline and 4.2 mL (30 mmol) of triethylamine in 50 mL of THF was added 4.18 mL (26 mmol) of pivaloyl chloride. After stirring for 10 min. at 0° C. the mixture was warmed to ambient temperature and poured into 0.5N HCl. The mixture was extracted with 100 mL of ether, and the organic extract was washed sequentially with NaHCO₃ and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel (elution with 3:1 hexanes-ether) to give, after removal of solvent, 5.2 g (92%) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide as a pale pink solid (IX), mp 70.5-71° C. 1H NMR (300 MHz, CDCl₃) δ 8.36(t, 1H, J=8.4 Hz); 7.57(br. s, 1H); 7.10-7.17(m, 2H); 1.30(s, 9H). ¹⁹ F NMR (282 MHz, CDCl₃) δ -129.8. High resolution mass spec: calculated for C₁₁ H₁₄ NOClF(M+H)⁺ : 230.0748, found: 230.0760.

Part B: Preparation of 2'-(Trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone

To a stirred, cooled (-50° C.) solution of 0.92 g (4.0 mmol) of 4'-chloro-2'-fluoro-2,2-dimethylpropionanilide in 10 mL of THF was added 2.5 mL (4.2 mmol) of 1.7 M t-BuLi in pentane over 5 min. The solution was stirred for 5 min. and treated with 1.0 mL (8.4 mmol) of ethyl trifluoroacetate over 2 min. The reaction was warmed to ambient temperature, stirred 15 min., and quenched with IN aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed sequentially with water then brine. The solution was dried(MgSO₄) and concentrated under reduced pressure to give an oil. The crude amide was chromatographed on silica gel (elution with 3:1 hexanes-ether followed by 1:1 hexanes-ether) to give 570 mg (43%) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an off-white solid. ¹ H NMR(300 MHz, CDCl₃) δ 8.68(s, 1H); 7.45-7.47(m, 1H); 7.08(dd, 1H, J=9.5, 2.6 Hz); 1.3(s, 9H). High resolution mass spec: calculated for C₁₃ H₁₃ NO₂ ClF₄ (M+H)⁺ : 326.0571, found: 326.0579.

Part C: Preparation of 2'-Amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone

A stirred solution of 0.35 g (1.07 mmol) of 2'-(trimethylacetamido)-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3 (mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K₂ CO₃. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give 240 mg (92%) of 2'-amino-5'-chloro-3'-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. ¹ H NMR (300 MHz, CDCl₃) δ 7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C₈ H₄ NOClF₄ (M⁺): 240.9918, found: 240.9914. ¹⁹ F NMR (282 MHz, CDCl₃) δ -132.7 (s, 1F), -70. 6(s, 3F).

Part D: Preparation of (+/-)-2-Amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl )benzyl alcohol

To a stirred, cooled (0° C.) solution of 2.0 mL (7.0 mmol) of 3.5 M cyclopropylacetylene in toluene was added 2 mL of THF followed by 2.8 mL (7.0 mmol) of 2.5 M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at 0° C., warmed to RT, and stirred a further 20 min. The reaction was cooled to 0° C. and treated with a solution of 300 mg (1.24 mmol) of 2'-amino-5-chloro-3'-fluoro-2,2,2-trifluoroacetophenone in 3 mL of THF over 2 min. The solution was stirred an additional 10 min. and the cold bath was removed. The reaction was stirred 5 min and poured into 0.5 N citric acid. The mixture was extracted with ether, and the organic extract was washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel (elution with hexanes then 3:1 hexanes-ether) afforded 185 mg (49%) of (+/-)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol as an off-white solid, mp 131-135° C. ¹ H NMR (300 MHz, CDCl₃) δ 7.34-7.36(m, 1H); 7.04(dd, 1H, J=10.4, 2.4 Hz); 4.58(br. s, 2H); 3.82(br. s, 1H); 1.35-1.44(m, 1H); 0.80-0.99(m, 4H). ¹⁹ F NMR (282 MHz, CDCl₃) δ -131.5(s, 1F), -80.5(s, 3F). High resolution mass spec: calculated for C₁₃ H₁₁ NOClF₄ (M+H)⁺ : 308.0470, found: 308.0465.

Part E: Preparation of (+/-)-6-Chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled (-25° C.) solution of 144 mg (0.47 mmol) of (+/-)-2-amino-5-chloro-3-fluoro-α-(cyclopropylethynyl)-α-(trifluoromethyl)benzyl alcohol in 6 mL of toluene was added 0.28 mL (2.0 mmol) of triethylamine followed by 0.62 mL(1.2 mmol) of a 1.93 M solution of phosgene in toluene over 3 min. The solution was stirred an additional 30 min. at -250° C. after which time it was warmed to ambient temperature and quenched with 0.5 N aq. citric acid. The mixture was extracted once with ether and once with ethyl acetate, and the combined organic extracts were washed sequentially with sat'd aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), and concentrated under reduced pressure to afford a tan solid. The crude product was chromatographed on silica gel(elution with 3:1 hexanes-ether) to afford, after concentration, 90 mg (58%) of (+/-)-6-chloro-4-(cyclopropylethynyl)-8-fluoro-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid. ¹ H NMR (300 MHz, CDCl₃) δ 7.65(br s, 1H); 7.32-7.34(m, 1H); 7.22(d, 1H, J=2.2 Hz); 1.36-1.43(m, 1H); 0.82-0.98(m, 4H). ¹⁹ F NMR (282 MHz, CDCl₃) δ -132.5(s, 1F), -81.1(s, 3F). High resolution mass spec: calculated for C₁₄ H₉ NO₂ ClF₄ (M+H)⁺ : 334.0258, found: 334.0244.

Example 5 Preparation of (+/-)-4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-5-methylbenzoyl N-methoxymethylamide.

To a solution of 2-amino-5-methylbenzoic acid (7.6 g, 50.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (12.5 g, 60.4 mmol) in acetonitrile (80 mL) were added triethylamine (15.8 mL, 60.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (10.3 g, 55.3 mmol) and the mixture was stirred at room temperature for 5 hours. At the end of the stirring, methylene chloride (200 mL) was added and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give a yellow syrupy residue. It was purified by column chromatography on silica gel with elution by 15:85 ethyl acetate-hexane to give pure 2-amino-5-methylbenzoyl N-methoxy-methylamide.

Part B: Preparation of 2-Amino-5-methylphenylisopropylketone.

To a solution of 2-amino-5-methylbenzoyl N-methoxymethylamide (472.6 mg, 2.4 mmol) in dry THF (3 mL) at -20° C. were added diisopropylethylamine (0.84 mL, 4.8 mmol) and chlorotrimethylsilane (0.61 mL, 4.8 mmol) dropwise and the mixture was stirred for 1 hour at -20˜5° C. It was then cooled to -200° C. again and was added 2M-isopropyl magnesium chloride in THF (4.8 mL, 9.6 mmol) dropwise. The mixture was stirred for 1.5 hours at -20˜10° C. After cooling to 0° C. was added saturated ammonium chloride and extracted with EtOAc. The organic layer was washed with 1N-HCl, water, saturated sodium bicarbonate and water, and dried over anhydrous sodium sulfate. It was evaporated in vacuo to give an oily residue. Column chromatography on silica gel with elution by 1:9 ethyl acetate-hexane afforded pure 2-amino-5-methylphenylisopropylketone (201 mg) as an oil.

Part C: Preparation of 2-Amino-5-methyl-α-cyclopropylethynyl-α-isopropyl-benzyl alcohol.

To a solution of cyclopropylacetylene (105 mg, 1.59 mmol) in THF (3 mL) at -20° C. was added 1.6M-nBuLi in hexane (0.96 mL, 1.54 mmol) dropwise and the mixture was stirred at the same temperature for 0.5 hours. Then a solution of 2-amino-5-methylphenylisopropylketone (94.5 mg, 0.53 mmol) in THF (3 mL) was added and the mixture was stirred for 5 hours at -20˜0° C. The reaction was quenched with saturated NH₄ Cl and the product was extracted with ethyl acetate. After washing with brine, the extract was dried over anhydrous sodium sulfate and evaporated to give the crude amino-alcohol as an oil.

Part D: Preparation of 4-Cyclopropylethynyl-4-isopropyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at -20° C. were added diisopropylethylamine (0.29 mL, 1.89 mmol) and 0.31 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at -20˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) provided pure titled compound (38 mg).

Example 6 Preparation of (+/-)-4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Iodo-4-methylaniline.

To a stirred solution of p-toluidine (5 g, 46.7 mmol) in methylene chloride (25 mL) was added a solution of sodium bicarbonate (4.7 g, 56 mmol) in water (75 mL). Then was added iodine (11.26 g, 44.33 mmol) in small portions and the mixture was stirred for 16 hours at room temperature. The reaction was quenched with saturated NaHSO₃ and the product was extracted with methylene chloride. The methylene chloride layer was washed with brine, dried over Na₂ SO₄, and evaporated in vacuo to give a crude 2-iodo-4-methylaniline.

Part B: Preparation of Trimethylacetyl 2-iodo-4-methylanilide.

To a stirred mixture of 2-iodo-4-methylaniline (46.7 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride dropwise over a period of 15 minutes and the mixture was stirred vigorously for 45 minutes at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂ SO₄. Evaporation of the solvent in vacuo afforded the pivaloyl amide as a solid. It was recrystallized from ethyl acetate and hexane.

Part C: Preparation of Trimethylacetyl 4-methyl-2-trifluoroacetylanilide.

To a stirred solution of trimethylacetyl 2-iodo-4-methylanilide (10.7 g, 33.75 mmol) in 50 mL of dry THF at -78° C. was added 1.6M-nBuLi in hexane (48.5 mL, 77.6 mmol) dropwise and the mixture was stirred for an hour at the same temperature. Then ethyl trifluoroacetate (9.6 mL, 81 mmol) was added dropwise and the mixture was stirred for 0.5 hours at -78° C. At the end of the stirring saturated NH₄ Cl solution was added and the mixture was warmed up to room temperature. The product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂ SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g, 13% yield) and trimethylacetyl 4-methylanilide (major product).

Part D: Preparation of 4-Methyl-2-trifluoroacetylaniline.

To a solution of trimethylacetyl 4-methyl-2-trifluoroacetylanilide (1.29 g) in 10 mL of dimethoxyethane was added 6N-HCl (5 mL) and the mixture was refluxed for 2.5 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO₃. The product was extracted with ethyl acetate, washed with brine, and dried over Na₂ SO₄. Evaporation of the solvent provided the aniline as a yellow solid in near quantitative yield.

Part E: Preparation of 2-Amino-5-methyl-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To stirred solution of 3-methyl-1-butyne (0.26 mL, 2.59 mmol) in 5 mL of dry THF at -20° C. was added 1.6M-nBuLi in hexane (1.4 mL, 2.24 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 1 hour with stirring. It was the cooled back to -20° C. and was added dropwise a solution of 4-methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for an hour at -20˜0° C. was added saturated NH₄ Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂ SO₄. The solvents were evaporated off to give crude amino-alcohol as a yellow solid residue.

Part F: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-6-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of the crude amino-alcohol (0.74 mmol) in dry toluene (7.5 mL) at -20° C. were added diisopropylethylamine (0.39 mL, 2.22 mmol) and 0.42 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1 hour at -20˜0° C. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. Column chromatography on silica gel (2:8 EtOAc-hexane) and recrystallization (EtOAc and hexane) provided pure titled compound (61 mg, 28% yield for 2 steps) as white crystals, mp 198-199° C.

Example 7 Preparation of (+/-)-6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Amino-3-iodo-acetophenone.

To a solution of 4-aminoacetophenone (5 g, 37 mmol) in 15 mL of CH₂ Cl₂ and 75 mL of water was added sodium bicarbonate (3.73 g, 44.4 mmol) followed by iodine (8.92 g, 35.1 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction was quenched by portionwise addition of sodium bisulfite until the iodine color disappeared. The product was extracted with CH₂ C₁₂, washed with water, dried over Na₂ SO₄. Evaporation of the solvent gave crude 4-amino-3-iodo-acetophenone as solid (7.92 g).

Part B: Preparation of Trimethylacetyl 2-iodo-4-acetylanilide.

To a stirred mixture of 4-amino-3-iodo-acetophenone (7.92 g, 30.3 mmol) in chloroform (50 mL) and 50 mL of saturated sodium carbonate was added trimethylacetyl chloride (7.8 mL, 63.7 mmol) dropwise over a period of 15 minutes and the mixture was stirred vigorously for 16 hours at room temperature. The product was extracted with chloroform, washed with water and dried over Na₂ SO₄. Evaporation of the solvent in vacuo afforded the pivaloyl amide as a brown oil. It was column chromatographed (silica gel, 1:9 EtOAc-hexane) to afford pure trimethylacetyl 2-iodo-4-acetylanilide (5.83 g) as white crystals.

Part C: Preparation of Trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide.

To a stirred solution of trimethylacetyl 2-iodo-4-acetylanilide (2.9 g, 8.45 mmol) and 1,3-propanedithiol in 25 mL of THF at 0° C. was added borontrifluorate etherate (0.63 mL, 5.1 mmol) and the mixture was stirred for 16 hours at room temperature. Then was added second portion of borontrifluorate etherate (0.63 mL, 5.1 mmol) and it was continued to stir for 44 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water saturated NaHCO₃ and brine, dried over MgSO4 and evaporated to a clear oil. It was column chromatographed (silica gel, 5:95 EtOAc-hexane) to give pure thioaketal as a foamy solid (2.85 g).

Part D: Preparation of Trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide.

To a stirred solution of trimethylacetyl 2-iodo-4-(2-methyl-1,3-dithian-2-yl)anilide (2.29 g, 5.26 mmol) in 20 mL of dry THF at -78° C. was added 1.6M-nBuLi in hexane (6.7 mL, 10.7 mmol) dropwise and the mixture was stirred for 45 minutes at the same temperature. Then ethyl trifluoroacetate (12.6 mL, 105.2 mmol) was added dropwise and the mixture was gradually warmed up to room temperature over a period of 3 hours. At the end of the stirring saturated NH₄ Cl solution was added, and the product was extracted with ethyl acetate, washed with water and brine, and dried over Na₂ SO₄. The solution was concentrated and the residue was column chromatographed on silica gel (1:9 EtOAc-hexane) to give the desired trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) and trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)anilide (1.33 g).

Part E: Preparation of 4-(2-Methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline.

To a solution of trimethylacetyl 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylanilide (0.63 g) in 10 mL of methanol was added 6N-HCl (2 mL) and the mixture was refluxed for 4 hours with stirring. After cooling it was poured over ice and was made basic with saturated NaHCO₃ The product was extracted with ethyl acetate, washed with brine, and dried over Na₂ SO₄. Evaporation of the solvent provided the desired 4-(2-methyl-1,3-dithian-2-yl)-2-trifluoroacetylaniline as a bright yellow solid.

Part F: Preparation of 2-Amino-5-(2-methyl-1,3-dithian-2-yl)-α-cyclopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To stirred solution of cyclopropylacetylene (122 mg, 1.9 mmol) in 5 mL of dry THF at -20° C. was added 1.6M-nBuLi in hexane (0.99 mL, 1.59 mmol) dropwise and the mixture was warmed up to 0° C. over a period of 45 minutes with stirring. It was the cooled back to -20° C. and was added dropwise a solution of ⁴ -methyl-2-trifluoroacetylaniline (150 mg, 0.74 mmol) in 2 mL of THF. After stirring for 1.5 hours at -20˜0° C. was added saturated NH₄ Cl (˜5 mL), and the product was extracted with ethyl acetate, washed with brine and dried over Na₂ SO₄. The solvents were evaporated off to give crude amino-alcohol as a bright yellow solid residue.

Part G: Preparation of 4-Cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of the crude amino-alcohol (0.53 mmol) in dry toluene (5 mL) at -20° C. were added diisopropylethylamine (0.28 mL, 1.59 mmol) and 0.3 mL of 20% solution of phosgene in toluene dropwise and the mixture was stirred for 1.5 hours at -20˜0° C. and for 5 minutes at room temperature. After addition of water (5 mL) it was extracted with ethyl acetate and the organic layer was washed with brine. It was dried over Na₂ SO₄ and evaporated in vacuo to give an oily residue. It was purified by preparative TLC on a silica gel plate (3:7 EtOAc-hexane) to give pure titled compound (77 mg).

Part H: Preparation of 6-Acetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a stirred solution of 4-cyclopropylethynyl-4-trifluoromethyl-6-(2-methyl-1,3-dithian-2-yl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (64 mg, 0.154 mmol) in 5 mL of methanol and 0.5 mL of water were added mercuric chloride (92 mg, 0.339 mmol) and mercuric oxide (50 mg, 0.23 mmol), and the mixture was refluxed for 2 hours. After cooling it was filtered through Celite and rinsed with EtOAc. The filtrate was washed with water and brine, dried over MgSO₄, and evaporated to give an oily residue. Column chromatography (silica gel, 2:8 EtOAc-hexane) afforded pure 6-6cetyl-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Example 8 Preparation of (+/-)-5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.73 g, 10.7 mmol) in dry THF (5 mL) at -20° was added 1.6M-nBuLi in hexane dropwise and the mixture was stirred for 15 minutes at the same temperature. Then a solution of 2,3-difluoro-6-triphenylmethylamino-α,α,α-trifluoroacetophenone (1 g, 2.14 mmol) in 5 mL of THF was added dropwise at -20° C. After stirring for 10 minutes, the cooling bath was removed and it was allowed to warm up to room temperature. The mixture was stirred for 45 minutes and was poured into saturated NH₄ Cl. The product was extracted with ether, washed with saturated NaHCO₃ and brine and dried over MgSO₄. Evaporation of solvent gave an oily residue, which was crystallized from methanol, ether and hexane mixture to provide pure product (0-432 g, 37.6%).

Part B: Preparation of 2,3-Difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 2,3-difluoro-6-triphenylmethylamino-α-1-(3-methyl)-1-butynyl-α-trifluoromethyl-benzyl alcohol (0.431 g, 0.8 mmol) in 5 mL of dry THF was added 1M-lithium aluminumhydride in THF (2.41 mL, 2.41 mmol) at room temperature and the mixture was stirred for 1 hour. The reaction was quenched with several drops of saturated NH₄ Cl and was added about 20 mL of ether. After stirring for 10 minutes it was washed with saturated NaHCO₃ and dried over MgSO₄. Evaporation of the solvent gave the desired transolefinic compound in near quantitative yield.

Part C: Preparation of 6-Amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol.

A solution of the crude product of step 2 (0.8 mmol) and 1.33 mL of c-HCl in methanol (5 mL) was stirred for 1 hour at room temperature and basified with saturated NaHCO₃. It was extracted with ether and washed with brine. After drying over MgSO₄, the solvent was evaporated off to give an oily residue. It was crystallized from hexane to give pure 6-amino-2,3-Difluoro-α-1-(3-methyl)-1-butenyl-α-trifluoromethyl-benzyl alcohol (0.184 g, 78%).

Part D: Preparation of 5,6-Difluoro-4-(3-methyl)-1-buten-1-yl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of the crude amino-alcohol (0.13 g, 0.44 mmol) in dry toluene (5 mL) at 0° C. were added diisopropylethylamine (0.23 mL, 1.32 mmol) and 0.24 mL of 2M-phosgene in toluene (0.48 mmol) dropwise and the mixture was stirred for 5 minutes at 0° C. and for 30 minutes at room temperature. After addition of saturated NH₄ Cl (5 mL) it was extracted with ether and the organic layer was washed with brine. It was dried over MgSO₄ and evaporated in vacuo to give an oily residue. It was purified by column chromatography on Silica gel (1:9 ether-hexane) to give pure titled compound (0.051 g, 36%).

Example 9 Preparation of (+/-)-4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of N-trimethylacetyl-3,4-difluoroanilide.

To a solution of 3,4-difluoroaniline (19 mL, 191 mmol) in methylene chloride (500 mL) at 0° C. was added triethylamine (32 mL, 230 mmol) followed dropwise with trimethylacetyl chloride (24 mL, 191 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 3 h. The reaction mixture was poured onto 3N HCl and extracted with methylene chloride (3×100 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. The residue was taken up in hexanes (300 mL) and filtered through a sintered glass funnel. The solids are washed thoroughly with hexanes (500 mL) and dried under vacuum to give 37.36 g of the pivaloyl amide as a solid (40.68 g theoretical, 92% yield).

Part B: Preparation of N-Trimethylacetyl 5,6-difluoro-2-trifluoroacetylanilide.

To a solution of N-trimethylacetyl-3,4-difluoroanilide (4.0 g, 14.6 mmol) in THF (60 mL) at -78° C. was added dropwise 1.6M nBuLi in hexane (22 mL, 35 mmol) and the resulting reaction mixture was allowed to stir at -78° C. for 1 h. The Ethyl trifluoroacetate (4 mL, 33.6 mmol) is added to the reaction mixture and the resulting solution was allowed to stir with warming to room temperature (ice bath removed after the addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part C: Preparation of 5,6-Difluoro-2-trifluoroacetylaniline.

To a solution of the orange oil in DME (15 mL) was added 6N HCl (75 mL) and the resulting mixture was allowed to reflux for 2 h. The reaction mixture was cooled, made basic with solid Na₂ CO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 2110 mg of 5,6-Difluoro-2-trifluoroacetylaniline as a yellow solid (3285 mg theoretical, 64% yield).

Part D: Preparation of ² -Amino-5,6-difluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.36 mL, 3.56 mmol) in THF (6 mL) at 0° C. was added 1.6M nBuLi in hexane (2.2 mL, 3.56 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5,6-Difluoro-2-trifluoroacetylaniline (200 mg, 0.89 mmol) in THF (6 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ C₁ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part E: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5,6-difluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of amino-alcohol (crude product, 1.21 mmol) in toluene (4 mL) at 0° C. was added N,N-diisopropylethylamine (0.54 mL, 3.12 mmol) followed by a solution of 1.93M phosgene in toluene (0.6 mL, 1.16 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 45 mg of the title compound (284 mg theoretical, 16% yield).

Example 10 Preparation of 2-Trifluoroacetylaniline

Part A: Preparation of 2-Amino-α-trifluoromethyl-benzyl alcohol.

To a solution of amino ketone (155 mg, 0.7 mmol) in methanol (2 mL) at room temperature was added Pd(OH)₂ (20 mg) and hydrogenated (H₂ /balloon) for 2 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The solids were triturated with ether (20 mL) and dried in vacuo to give 117 mg of 2-Amino-α-trifluoromethyl-benzyl alcohol as a pale yellow solid. (134 mg theoretical, 87% yield).

Part B: Preparation of 2-Trifluoroacetylaniline.

To a slurry of amino alcohol (520 mg, 2.72 mmol) in methylene chloride (5 mL) at room temperature was added MnO₂ (10×wt, 5 g) and the resulting reaction mixture was allowed to stir at room temperature for 0.75 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give an orange oil which is used without further purification due to instability of compound.

Example 11 Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline

Part A: Preparation of 2-Amino-6-fluoro benzoyl N-methoxy-methylamide.

To a solution of 2-amino-6-fluorobenzoic acid (5 g, 32.26 mmol) in AcCN (100 mL) at room temperature was added N,O-dimethylhydroxylamine hydrochloride (3.8 g, 38.71 mmol), EDAC (7.4 g, 38.71 mmol) followed by triethylamine (5.38 mL, 38.71 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 6 h. The reaction mixture was poured onto saturated NaHCO₃ and extracted with EtOAc (3×100 mL). The combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 25% EtOAc-hexanes eluant) provided 4.29 g of the desired compound (5.87 g theoretical, 73% yield).

Part B: Preparation of 2-Triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide.

To a solution of 2-amino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 2.14 mmol) in methylene chloride (10 mL) at room temperature was added N,N'-diisopropylamine (1.2 mL, 6.4 mmol) followed by triphenylmethyl bromide (830 mg, 2.57 mmol) and the resulting reaction mixture is allowed to stir at room temperature for 0.5 h. The reaction mixture was poured onto water and extracted with methylene chloride (3×50 mL) and the combined organic extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 832 mg of the desired compound (942 mg theoretical, 88% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluorobenzaldehyde.

To a solution of 2-triphenylmethylamino-6-fluorobenzoyl N-methoxy-methylamide (300 mg, 0.68 mmol) in THF (4 mL) at -78° C. was added lithium aluminum hydride (30 mg, 0.82 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (dry ice bath removed after addition of reagent) for 1 h. The reaction mixture was quenched with 20% KHSO₄ and extracted with EtOAc (3×100 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 182 mg of the title compound (260 mg theoretical, 70% yield).

Part D: Preparation of 2-Amino-6-fluoro-α-trifluoromethyl-benzyl alcohol.

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part E: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline.

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Example 12

Preparation of (+/-)-4-Cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 5-(t-Butoxycarbonylamino)-2-chloropyridine.

To a stirred solution of 2.83 g(22.0 mmol) of 5-amino-2-chloropyridine in 20 mL of anhydrous THF was added 44.0 mL(44.0 mmol) of a 1.0M solution of NaHMDS in toluene over 5 min. The dark solution was stirred 15 min. and 4.36 g(20 mmol) of di-t-butyldicarbonate in 5 mL of THF was introduced over 2 min. The thick mixture was stirred an additional 1 h and poured into 0.5N aq. HCl. The solution was extracted with ethyl acetate, and the organic extract was washed with saturated aq. NaHCO₃, water, and brine. The solution was dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel(gradient elution with 3:1 hexanes-ether then ether) to give, after evaporation of solvents, 3.81 g(83%) of 5-(t-butoxycarbonylamino)-2-chloropyridine as a white solid, mp 122-123° C. ¹ H NMR(300 MHz, CDCl₃) δ 8.23(d, 1H, J=2 Hz); 7.98(br. d, 1H, J=8 Hz); 7.25(d, 1H, J=8 Hz); 6.58(s, 1H); 1.52(s, 9H).

Part B: Preparation of 2-(5-(t-Butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol.

To a stirred, cooled (-50° C.) solution of 643 mg(2.8 mmol) of 5-(t-butoxycarbonylamino)-2-chloropyridine in 8 mL of anhydrous THF was added 4.7 mL(7.0 mmol) of t-BuLi in pentane over 3 min. The solution was stirred an additional 35 min. at -50° C. after which time 1 mL(large excess) of 4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-one. The solution was stirred an additional 20 min., warming to ambient temperature. The reaction was poured into 10% aq. citric acid, and the mixture was extracted with 1:1 ether-ethyl acetate. The organic extract was washed with saturated aq. NaHCO₃, then brine, dried (MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel(gradient elution with 6:1 then 3:1 hexanes-ethyl acetate) afforded, after removal of solvent, 620 mg(56%) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol as an amorphous solid. Mass spec.(NH₃ -CI): 391((M+H)⁺, 100%); 291((M+H-t-Boc)⁺, 49%). ¹ H NMR(300 MHz, CDCl₃) δ 9.08(br. s, 1H); 8.19(br. s, 1H); 7.59(s, 1H); 1.50(s, 9H); 1.37-1.43(m, 1H); 0.81-0.97(m, 4H).

Part C: Preparation of 4-Cyclopropylethynyl-6-chloro-4 trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a stirred solution of 230 mg(0.59 mmol) of 2-(5-(t-butoxycarbonylamino)-2-chloropyrid-4-yl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol in 6 mL of anhydrous toluene was added 0.92 mL of a 2.5M solution of n-BuLi in hexanes. The solution was brought to reflux and stirred 10 min. after which time an additional 0.10 mL of n-BuLi was added. The solution was stirred an additional 20 min. at reflux and cooled to ambient temperature. The reaction was poured into 10% aq. citric acid and extracted with ether. The organic extract was washed with brine, dried(MgSO₄), and concentrated under reduced pressure. Chromatography on silica gel(elution with 3:1 hexanes-ethyl acetate) afforded 25 mg (13%) of 4-cyclopropylethynyl-6-chloro-4-trifluoromethyl-7-aza-1,4-dihydro-2H-3,1-benzoxazin-2-one as an amorphous solid. Mass spec. (NH₃ -CI): 334((M+NH₄)⁺, 100%); 317((M+H)⁺, 100%); 273((M+H--CO₂)⁺, 21%). ¹ H NMR(300 MHz, CDCl₃) δ 9.62(br. s, 1H); 8.17(s, 1H); 7.44(s, 1H); 1.36-1.44(m, 1H); 0.82-0.99(m, 4H).

Example 13 Preparation of (+/-)-6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 4-Chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a stirred, gently refluxing solution of 7.0 g(31.9 mmol) of 2-amino-5-methoxy-(1,',1',1'-trifluoro)acetophenone in 27 mL of anhydrous toluene was added 24.8 mL(47.9 mmol) of a 1.93M solution of phosgene in toluene over 2 min. (Note: A dry ice-acetone cold finger is used to condense phosgene during this reaction.). The solution is warmed at reflux for 2 h, cooled, and charged with 15 mL of hexanes. Upon stirring overnight at ambient temperature a precipitate formed which was filtered, washed with hexanes, and briefly air-dried to give 5.06 g(60%) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as an off-white solid mp 112-114° C. ¹ H NMR(300 MHz, CDCl₃) δ 9.05(br. s, 1H); 7.07(br. s, 1H); 7.02(dd, 1H, J=8, 2 Hz); 6.90(d, 1H, J=8 Hz); 3.83(s, 3H).

Part B: Preparation of 6-Chloro-4-(2-methoxyethoxy)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 0.15 mL of 2-methoxyethanol in 5 mL of anhydrous THF at ambient temperature was added 20 mg of 100% sodium hydride. After 20 min, 100 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone was added, and the resulting solution was stirred at ambient temperature for 30 min. The reaction mixture was poured onto aqueous ammonium chloride and was extracted with ethyl acetate. The organic extracts were washed with brine, dried and evaporated. The crude product was purified by preparative TLC on silica gel (elution with ethyl acetate/hexanes 1:1) to afford a material which was crystallized from ethyl acetate-hexanes to afford 81 mg (71%) of the title compound.

Example 14 Preparation of (+/-)-6-Chloro-4-propylamino-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 230 mg of 4,6-dichloro-4-(trifluoromethyl)benzoxazinone in 20 mL of dry ether was added 0.250 mL of n-propylamine. After stirring 30 min at ambient temperature, the solution was partitioned between ether and water, and the organic layer was washed with brine, dried, and evaporated. The crude product was purified by column chromatography on silica gel (elution with ethyl acetate-hexanes 1:3) to afford after crystallization from hexanes 24 mg (9.7%) of the title compound.

Example 15 Preparation of (+/-)-6-Chloro-4-[2-(furan-2-yl)ethynyl]-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of 5.9 g (25 mmoles) of 1,1-dibromo-2-(furan-2-yl)ethylene in 124 mL of anhydrous THF at -20° was added dropwise 31.0 mL of 1.6 M n-butyllithium in hexanes (50 mmoles). This solution was allowed to warm to ambient temperature over a period of 30 min, after which time it was cooled to -50°. 4,6-Dichloro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one (2.65 g, 9.27 mmoles) was added in one portion, and the resulting solution was allowed to warm to -35° over 40 min. The reaction was quenched by the addition of aqueous ammonium chloride, and this mixture was poured onto water and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and evaporated. The crude product was purified by column chromatography on silica gel (elution with 15% and 30% ethyl acetate in hexanes) affording 3.5 g of a solid which was recrystallized from ethyl acetate/hexanes to afford 3.03 g (95.7%) of the title compound.

Example 16 Preparation of (+/-)-4-(1-Butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled(-78° C.) solution of 0.5 g(excess) of 1-butyne in 3 mL of anhydrous THF was added 1.6 mL(4.0 mmol) of a 2.5M solution of n-BuLi in hexanes over 3 min. The solution was stirred 5 min. and charged with 266 mg(1.00 mmol) of 4-chloro-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a single portion. The solution was warmed to -10° C. over 20 min., whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was recrystallized from ethyl acetate-hexanes to afford 144 mg(48%) of 4-(1-butynyl)-6-methoxy-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 161-162° C. ¹ H NMR(300 MHz, CDCl₃) δ 8.81(br. s, 1H); 7.07(d, 1H, J=2 Hz); 6.94(dd, 1H, J=9, 2 Hz); 6.81(d, 1H, J=8 Hz); 3.82(s, 3H); 2.34(q, 2H, J=7 Hz); 1.22(t, 3H, J=7 Hz).

Example 17 Preparation of (+/-)-4-(1'-hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR35## Part A: Preparation of Methyl 1-hydroxy-1-cyclopropanecarboxylate.

1-Hydroxy-1-cyclopropanecarboxylic acid (587 mg, 5.75 mmol) was dissolved in methanol (20 mL) under nitrogen. Thionyl chloride (4 drops) were added and the reaction was stirred overnight at room temperature. Triethylamine was then added until the reaction was alkaline as judged by moistened pH paper. The solvent was then removed on the rotary evaporator.

Part B: Preparation of Methyl 1-triisopropylsilylhydroxy-1-cyclopropanecarboxylate.

The residue was then dissolved in dry methylene chloride (20 mL) under a nitrogen atmosphere. Dry 2,6-lutidine (distilled from calcium hydride, 1.0 mL, 8.62 mmol) was added and the reaction cooled to 0° C. Trilsopropylsilyl trifluoromethanesulfonate (2.3 mL, 8.62 mmol) was then added dropwise and stirring continued for 1 hour. The reaction was then poured into 1 N HCl and extracted with hexanes. The organic layer was washed successively with water and brine, then dried with magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography (silica) using 19:1 hexanes/ethyl acetate. This provided the silyl methyl ester in 87% yield for two steps (1.35 g).

Part C: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanemethanol.

The silyl methyl ester (1.05 g, 3.86 mmol) was dissolved in hexane (12 mL) under nitrogen. The reaction was cooled in a dry ice/acetone bath and a solution of diisobutylaluminum hydride (1.5 M in toluene, 6.4 mL, 9.64 mmol) was introduced dropwise. Stirring was continued for 2 hours when the reaction was quenched by the addition of methanol (12 mL). The reaction was warmed to room temperature and poured into a saturated aqueous solution of sodium potassium tartrate. The clarified solution was extracted with ether and the organic layer washed with water and brine. After drying over magnesium sulfate, the product was isolated by filtration and evaporation (894.4 mg, 95%). This material was of sufficient purity for direct use in the next step.

Part D: Preparation of 1-Triisopropylsilylhydroxy-1-cyclopropanecarboxaldehyde.

A 100 mL flask was flame-dried and sealed under nitrogen. The flask was charged with dry methylene chloride (11 mL) and oxalyl chloride (0.44 mL 5.07 mmol). The solution was cooled in a dry ice/acetone bath and dimethylsulfoxide was introduced (0.73 mL, (1.065 g, 4.36 mmol) was added as a solution in methylene cholride (5.0 mL). After stirring for 20 minutes, triethylamine (3.1 mL, 22.4 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was then poured into 1 N HCl and extracted with ether. The organic layer was washed twice with water and once with brine. Drying with magnesium sulfate, filtration and evaporation then provided the crude product. This material was of sufficient purity for use in the next step.

Part E: Preparation of 1-Triisopropylsilylhydroxy-1-(2',2'-dibromoethene)cyclopropane.

A 500 mL flask was charged with carbon tetrabromide (2.89 g, 8.72 mmol) dissolved in dry methylene chloride (87 mL). The solution was cooled to -20° C. when triphenylphosphine (recrystallized from hexanes, 2.28 g, 8.72 mmol) was added and stirring continued for 45 minutes. The reaction was then cooled to -60° C. where the crude aldehyde (maximum of 4.36 mmol) dissolved in dry methylene chloride (40 mL) containing triethylamine (0.61 mL, 4.26 mmol) was added. Stirring was continued overnight with warming to room temperature. The reaction was then diluted with hexanes (1 l) and filtered through a pad of magnesium sulfate. Evaporation and purification by flash column chromatography (silica, hexanes) gave the desired dibromoolefin (35%, 607.1 mg).

Part F: Preparation of (+/-)-4-(1'-Triisopropylsilylhydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

A 50 mL two-necked flasked was flame-dried in vacuo and sealed under nitrogen. The dibromoolefin was dissolved in dry tetrahydrofuran (8.0 mL) and transferred to the reaction flask. The reaction was cooled to -78° C. and a solution of n-butyllithium (2.5 M in hexanes, 1.2 mL, 2.96 mmol) was added dropwise. Stirring was continued for 20 minutes when a solution of the chlorobenzoxazinone (212 mg. 0.74 mmol) in dry tetrahydrofuran (2.0 mL) was added. The reaction was warmed to -60° C. and stirring continued for 30 minutes. The reaction was then poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine and then dried over magnesium sulfate. The crude product was isolated by filtration and evaporation. Flash chromatography (silica, 4:1 hexanes/ethyl acetate) gave the partially purified product (235 mg). A subsequent chromatography under similar conditions gave the desired material (35%, 118 mg) with suitable purity for the next step.

Part G: Preparation of 4-(1'-Hydroxy)-cyclopropylethynyl-4-trifluoromethyl-6-chloro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

The starting material (53.0 mg, 0.117 mmol) was dissolved in dry tetrahydrofuran (2.0 mL) under nitrogen. A solution of tetra-n-butylammonium fluoride (1M in tetrahydrofuran, 0.12 mL, 0.12 mmol) was added and stirring continued for 15 minutes. The reaction was then diluted with 1:1 hexanes/ethyl acetate and washed twice with water and once with brine. Drying with magnesium sulfate, filtration, and evaporation gave the crude product. The compound was purified by flash chromatography (silica, 4:1 hexanes/ethyl acetate to 2:1 hexanes/ethyl acetate). The desired product was isolated in 74% yield (28.7 mg). m.p. 192-194° C. HRMS: calculated for C₁₄ H₁₀ ClF₃ NO₃, M+H): 332.0301; found 332.0296.

Example 18 Preparation of (+/-)-4-isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Triphenylmethylamino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.16 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 5-fluoro-2-trifluoroacetyl-triphenylmethylaniline (300 mg, 0.67 mmol) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part B: Preparation of 2-Amino-5-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of the benzyl alcohol (crude product, approx. 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated hydrochloric acid (0.1 mL) and the resulting reaction mixture was allowed to stir at room temperature for 0.25 h. The reaction mixture was quenched with saturated NaHCO₃ and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes eluant) provided 103 mg of the title compound (184 mg theoretical, 56% yield over two steps).

Part C: Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of amino-alcohol (103 mg 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.30 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 0.1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

Example 19 Preparation of 4-Chloro-2-cyclopropylacetylaniline ##STR36##

Cyclopropyllithium was prepared by the procedure of Dakkouri (Chem. Ber. 1979, 112, 3523. ). To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a West condenser and a nitrogen line was charged 1.0 g (0.14 mol.) of freshly cleaned Li ribbon and 20 ml anhydrous ether. The mixture was cooled to 0° C. and 5.6 ml of cyclopropylbromide (70 mmol) in 10 ml of anhydrous ether was added dropwise. The bromide solution was added over 45 min. due to the exothermic nature of the metalation reaction. After the addition was complete the lithium reagent was aged for 30 min. then cooled to -65° C. A solution of 5.53 g (28 mmol.) of 5-chloroisatoic anhydride in 80 ml THF was prepared in a dry 3 neck flask and cooled to -40° C. The cyclopropyllithium solution was transferred via cannula into the anhydride solution over 30 min. The resulting milky solution was aged for 1 h at -40° C. during which time the solution became clear with a pale green color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a tacky yellow solid which was chromatographed on silica gel with ethyl acetate/ hexanes (3:1) to provide 3.56 g of the title compound in 65% yield. Crystallization from heptane provides the title compound as a pale yellow solid: m.p. 73.7° C.; ¹ H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=1.5 Hz, 1 H), 7.22 (dd, J=2.3, 8.7 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.13 (brs, 2H), 2.56 (m, 1 H),. 1.18 (m, 2 H), 1.00 (m, 2 H); ¹³ C. NMR (75 MHz, CDCl₃) δ 201.06, 148.23, 133.83, 130.41, 121.70, 119.69, 118.56, 17.37, 11.08; IR (cm⁻¹) 3315, 3012, 1628, 1582, 1533, 1481, 1464, 1414, 1389, 1343, 1313, 1217, 1183, 1158, 1082, 1053, 1032, 985, 893, 868, 813.

Example 20 Preparation of 4-Chloro-2-((cyclopropylenthynyl)acetyl)aniline ##STR37##

To a 3 neck 100 ml flask equipped with a magnetic stir bar, a thermocouple probe, a solid addition funnel and a nitrogen line was charged 3.7 g (56.0 mmol.) of cyclopropylacetylene and 30 ml of anhydrous THF. The solution was cooled to -60° C. and 30 ml (53.1 mmol.) of 1.8 M hexyllithium in hexanes was added dropwise while maintaining the internal temperature below -20° C. The solution was aged at -40° C. for 30 min. and then 5 g (25.3 mmol.) of 5-chloroisatoic anhydride was added as a solid in small portions. The resulting solution was aged for 2 h at -40° C. during which time the solution became clear with a pale yellow color. The anion solution was quenched by addition of 1 M citric acid solution and then warmed to ambient temperature. The phases were separated and the organic layer washed with water and concentrated to provide a an orange solid. The product was triturated with heptanes to provides 9 as a tan solid: ¹ H NMR (300 MHz, CDCl₃) δ 8.43 (m, 1 H), 8.02 (m, 1H), 7.36 (m, 1H), 1.48 (m, 1 H), 0.99 (m, 2 H), 0.87 (m, 2 H); IR (cm⁻¹) 2978, 2221, 1641, 1579, 1502, 1434, 1410, 1370, 1299, 1055, 906, 829, 731.

Example 21 Preparation of (S)-6-Chloro-4-(choro)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR38##

To a 3 neck flask equipped with a magnetic stirrer, a thermocouple probe and a dry ice condenser was charged 25 g (0.11 mol.) of trifluoroketone 3 and 150 ml of anhydrous toluene. This yellow solution was then heated to gentle reflux and a solution (87 ml, 0.17 mol.) of phosgene (1.93 M) in toluene was added subsurface. The solution was heated to reflux (temperature range at 104 to 110° C.) for 3 h after which time the yellow color had dissipated and the starting ketone was not detected by ¹ H NMR. The solution was cooled to ambient temperature and then concentrated to provide a heterogeneous solution. The product was triturated with heptane (100 ml) and filtered to provide 29.24 g (92%) of the desired chlorobenzoxazinone as a white solid. m.p. 140.8° C.; ¹ H NMR (300 MHz) δ 9.26 (b, 1H), 7.57 (s, 1H), 7.45 (dd, J=1.9, 8.3 Hz, 1H), 6.94 (d, J=8.7 Hz, 1H) ; ¹³ C NMR (75 MHz) δ 146.32, 132.88, 132.42, 130.27, 125.80, 122.83, 119.06, 116.79, 115.85, 0.013; ¹⁹ F NMR (282 MHz) δ -79.5; IR (cm⁻¹) 3191, 1764, 1601, 1498, 1403, 1335, 1316, 1252, 1199, 1073, 991, 901, 874, 826, 683.

Example 22 Preparation of (+/-)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR39##

To a 50 ml 3 neck flask equipped with a magnetic stir bar, a thermocouple probe and nitrogen inlet was charged 10 ml anhydrous THF and 2.2 eq cyclopropylacetylene (0.23 g, 3.4 mmol.). The solution was cooled to -50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 1.8 ml, 3.26 mmol.) was added dropwise via syringe. The internal temperature was maintained below -30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 0.44 g (1.55 mmol.) of the chlorobenzoxazinone in 5 ml THF was added dropwise. The reaction solution was maintained below -20° C. during the addition. The mixture was aged at -20° C. for 4 h after which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a light yellow solid. The product was then triturated with heptanes to provide 0.47 g (95 %) of racemic title product as a white solid. HPLC: 99.8 area %; m.p. 183-6° C; ¹ H NMR (400 MHz, DMSO-d₆) δ 11.05 (s, 1H), 7.54 (dd, J=2.5, 7 Hz, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.99 (d, J=7 Hz, 1H), 1.58 (m, 1H), 0.92 (m, 2H), 0.77 (m, 2H); ¹³ C NMR (100 MHz, DMSO-d₆) δ 146.23, 134.71, 132.04, 126.93, 126.57, 122.24, 116.83, 114.08, 95.63, 77.62, 65.85, 8.48, 8.44, -1.32; ¹⁹ F NMR (282 MHz, DMSO-d₆) δ --81.1; IR (cm⁻¹) 3316, 3094, 2250, 1752, 1602, 1498, 1196, 1186. HRMS calcd. for C₁₄ H₁₀ F₃ ClNO₂ (M+H) 316.0352, found 316.0338. Anal. Calcd. for C₁₄ H₉ F₃ ClNO₂ : C, 53.27; H, 2.87; N, 4.45; Cl 11.23; F, 18.05. Found: C, 53.15; H, 2.73; N, 4.37; Cl, 11.10; F, 17.84.

Example 23 Preparation of (S)-6-Chloro-4-(1-pyridylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR40##

To a 50 ml 3 neck flask equipped with a magnetic stir bar, thermocouple and nitrogen inlet was charged 20 ml anhydrous THF and 2.2 eq pyridylethyne (1.1 g, 10.2 mmol.). The solution was cooled to -50° C. and 2.0 eq. of n-hexyllithium in hexanes (1.8 M, 4.0 ml, 10.0 mmol.) was added dropwise via syringe. The internal temperature was maintained below -30° C. during the organolithium charge. The solution was aged for 30 minutes and then a solution of 1.5 g (5.2 mmol.) of the chlorobenzoxazinone from Example 21 in 15 ml THF was added dropwise. The reaction solution was maintained above -20° C. during the addition. The mixture was aged at -20° C. for 2 h at which time all of the starting material had been consumed by TLC. The mixture was then quenched while cold with saturated ammonium chloride solution and the layers separated. The organic solution was dried over sodium sulfate, concentrated to provide a brown solid. The product was purified by flash chromatography (hexanes/ethyl acetate; 3:1) and then triturated with heptanes to provide 1.06 g (57%) of the title compound as a white solid. HPLC: 99.8 area %; m.p. 185.8° C; ¹ H NMR (300 MHz) δ 9.62 (s, 1H), 8.68 (d, J=4.2 Hz, 1 H), 7.76 (dd, J=7.6, 9.5 Hz, 1H), 7.61 (d, J=5.7 Hz, 2H), 7.40 (m, 2 H), 6.91 (d, J=8.7 Hz, 1H; ¹³ C NMR (75 MHz) δ 150.38, 148.20, 140.32, 136.57, 133.43, 132.06, 129.34, 128.30, 127.60, 124.65, 123.94, 120.13, 116.37, 114.01, 88.72, 78.75; ¹⁹ F NMR (282 MHz) δ -81.4; IR (cm⁻¹)3245, 3157, 3069, 2946, 2876, 2252, 1757, 1603, 1581, 1498, 1467, 1428, 1401, 1305, 1256, 1243, 1186, 1142, 1401, 1304, 1256+, 1243, 1186, 1142, 1103, 1072, 1037, 997, 971, 940, 866, 822, 780, 740. MS FIA/PCI (M+H) 353 m/z.

Example 24 Preparation of (+/-)-6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one ##STR41## Part A: Preparation of 1-(t-Butyldimethylsilyl)-2-cyclopropylacetylene

To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5 M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH₄ Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39-42° C. at 0.5 torr). ¹ H NMR(CDCl₃, 300 MHz) δ 1.17-24(m, 1H); 0.95(s, 9H); 0.6-0.75(m, 4H); 0.00(s, 6H).

Part B: Preparation of 1-Deutero-1-ethynylcyclpropane

To a stirred, cooled(-30° C. ) solution of 130 g(720 mmol) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene in 400 mL of THF was added 403 mL(1.01 mol) of a 2.5 M solution of n-BuLi in hexanes over 15 min. The solution was stirred 1.5 h at -20° C. and then treated with 49 mL(1.2 mol) of CD₃ OD over 10 min. After stirring 10 min. at -10° C. the reaction was quenched with 10 mL of D₂ O, followed 15 min later with 1 L of 20% aq. citric acid. The mixture was extracted with 1 L of ether, and the organic extract was washed sequentially with water, sat'd aq. NaHCO₃, an d brine. The solution was dried(MgSO₄), concentrated under reduced pressure, and re-dissolved in 300 mL of THF. This solution was treated with 780 mL(350 mmol) of a 1 M solution of (n-Bu)₄ NF in THF and stirred 6 h at ambient temperature. The solution was cooled to 0° C., washed with 1 L of water, and the aqueous phase was extracted with 150 mL of p-xylene. The organic extract was washed with 500 ML of water, and the combined aqueous phases were extracted with 70 mL of p-xylene. The two organic phases were combined, and washed 5 times with water and once with brine, dried(MgSO₄), and distilled. The fraction which boiled up to 105° C. at ambient pressure was collected to give 88 g of a solution having a deuterocyclopropylacetylene concentration of c. 43%. The remainder is primarily THF with some xylene and some 1-butene.

Part C: Preparation of (+/-) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a stirred, cooled(-60° C.) solution of 12.6 g of a 60% solution of 1-deutero-1-ethynylcyclpropane in 65 mL of anhydrous THF was added 41 mL(102 mmol) of a 2.5M solution of n-BuLi in hexanes over 20 min. The solution was stirred 30 min. and charged with 9.7 g(33.9 mmol) of 4,6-dichloro-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in 10 mL of THF over 2 min. The solution was warmed to -30° C. over 1 h, whereupon it was quenched with 20% aqueous citric acid. The mixture was extracted with ether, and the organic extract was washed with saturated aq. NaHCO₃ then brine. The solution was concentrated under reduced pressure, and the crude product was chromatographed on silica gel(elution with 2:1 hexanes-ether) to afford 5.8 g(54%) of (+/-) 6-chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 180-181° C. ¹ H NMR(300 MHz, CDCl₃) δ 9.32(br. s, 1H); 7.50(m, 1H); 7.37(dd, 1H, J=8, 1 Hz); 6.95(d, 1H, J=8 Hz); 0.82-0.96(m, 4H). Chiral chromatographic resolution provides (-) 6-Chloro-4-(1-deuterocycloprop-1-ylethynyl)-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as a white solid, mp 133-134° C.

Example 25 Preparation of 4-Isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one

Part A: Preparation of 2-Amino-6-fluoro-α-trifluoromethyl-benzyl alcohol.

To a solution of 2-triphenylmethylamino-6-fluorobenzaldehyde (100 mg, 0.24 mmol) in THF (2 mL) at 0° C. was added trifluoromethyltrimethylsilane (0.06 mL, 0.36 mmol) followed by a solution of tetrabutylammonium fluoride in THF (1M, 0.36 mL, 0.36 mmol) and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after the addition of reagents) for 0.5 h. The reaction mixture was poured onto water and extracted with EtOAc (3×50 mL) and the combined EtOAc extracts were dried over anhydrous NaSO₄ and concentrated in vacuo. Chromatography (SiO₂, 10% EtOAc-hexanes) provided 88 mg of the title compound (108 mg theoretical, 82% yield).

Part B: Preparation of 3-Fluoro-2-trifluoroacetyl-triphenylmethylaniline.

To a solution of 2-amino-6-fluoro-α-trifluoromethyl-benzyl alcohol (88 mg, 0.2 mmol) in methylene chloride (6 mL) at room temperature was added manganese(IV)oxide (900 mg, 10×wt) and the resulting reaction mixture was allowed to stir at room temperature for 5 h. The reaction mixture is filtered through Celite and concentrated in vacuo. Chromatography (SiO₂, 5% EtOAc-hexanes) provided 52 mg of the title compound (90 mg theoretical, 58% yield).

Part C: Preparation of 2-Triphenylmethylamino-6-fluoro-α-isopropylethynyl-α-trifluoromethyl-benzyl alcohol.

To a solution of 3-methyl-1-butyne (0.15 mL, 1.51 mmol) in THF (2 mL) at 0° C. was added 1.6M nBuLi in hexane (0.84 mL, 1.34 mmol) and the resulting reaction mixture was allowed to stir at 0° C. for 0.5 h. A solution of 6-fluoro-2-trifluoroacetylaniline (300 mg, 0.67 mmol ) in THF (2 mL) was added to the reaction mixture and the resulting reaction mixture was allowed to stir with warming to room temperature (ice bath removed after addition of reagent) for 0.5 h. The reaction mixture was poured onto saturated NH₄ Cl and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo to give an orange oil. This product was used in the next step of the synthetic sequence without further purification.

Part D: Preparation of 4-isopropylethynyl-4-trifluoromethyl-5-fluoro-1,4-dihydro-2H-3,1-benzoxazin-2-one.

To a solution of the crude trityl protected amino-alcohol (crude product, 0.67 mmol) in methanol (5 mL) at room temperature was added concentrated HCl (0.1 mL) and the resulting reaction mixture is allowed to stir at room temperature for 0.25 h. The reaction mixture is concentrated in vacuo and the residue is taken up in ether (10 mL) and washed with saturated NaHCO₃. The ether extracts were dried over anhydrous MgSO4 and concentrated in vacuo. Chromatography (SiO₂, 15% EtOAc-hexanes) provided 103 mg of the deprotected amino-alcohol (184 mg theoretical, 56% yield).

To a solution of amino-alcohol (103 mg, 0.37 mmol) in toluene (3 mL) at 0° C. was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) followed by a solution of 1.93M phosgene in toluene (0.25 mL, 0.48 mmol) and the resulting solution was allowed to stir at 0° C. for 1 h. The reaction mixture was poured onto water and extracted with ether (3×50 mL). The combined ether extracts were dried over anhydrous MgSO₄ and concentrated in vacuo. Chromatography (SiO₂, 20% EtOAc-hexanes eluant) provided 89 mg of the title compound (111 mg theoretical, 80% yield).

                                      TABLE 1                                      __________________________________________________________________________       #STR42##                                                                        -                                                                                                           Mass                                             Ex. # G R.sup.1 R.sup.2 m.p. (° C.) Spec.                             __________________________________________________________________________     1   6-Cl,8-OH                                                                             CF.sub.3                                                                           C.tbd.C-cycPr    332.0301                                         2(-) 6-Cl,8-OH CF.sub.3 C.tbd.C-cycPr 170-172                                  3(-) 6-Cl,8-OH CF.sub.3 C.tbd.C-cycPr                                           4 6-Cl,8-F CF.sub.3 C.tbd.C-cycPr 169-171 334.0244                             5 6-CH.sub.3 iPr C.tbd.C-cycPr   138-138.5 270.1494                            6 6-CH.sub.3 CF.sub.3 C.tbd.C-iPr 198-199 298.1047                             7 6-COCH.sub.3 CF.sub.3 C.tbd.C-cycPr 197-200                                  8 5,6-diF CF.sub.3 3-methyl-1-                                                   buten-1-yl                                                                   9 5,6-diF CF.sub.3 C.tbd.C-iPr  319.0616                                      12 6-Cl,7-aza CF.sub.3 C.tbd.C-cycPr  317.0322                                 13 6-Cl CF.sub.3 methoxyethoxy                                                 14 6-Cl CF.sub.3 n-propylamino                                                 15 6-Cl CF.sub.3 furan-2-yl-.tbd.-                                             16 6-OMe CF.sub.3 C.tbd.C-Et 161-162 300.0841                                  17 6-Cl CF.sub.3 .tbd.-(1'-OH-cycPr)  332.0296                                 18 5-F CF.sub.3 .tbd.-iPr                                                      22 6-Cl CF.sub.3 .tbd.-cycPr  316.0352                                         23 6-Cl CF.sub.3 .tbd.-2-pyridyl  353                                               (M+H)                                                                     24 6-Cl CF.sub.3 .tbd.-(1-deutero- 133-134                                        cycloprop-1-yl)                                                             25 5-F CF.sub.3 .tbd.-iPr                                                      26 6-Cl,8-OMe CF.sub.3 C.tbd.C-cycPr  346.0477                                 27 6-Cl,7-OH CF.sub.3 C.tbd.C-cycPr  332.0286                                  28 6-Cl,8-F CF.sub.3 C.tbd.C-Et 191-192 339.0525                                    (M+NH.sub.4.sup.+)                                                        29 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2 160-162 340                                              (MH.sup.+)                                 30 5,6-diF CF.sub.3 C.tbd.C-cycPr  318.0550                                         (MH.sup.+)                                                                31 5,6-diF CF.sub.3 C.tbd.C-iPr amorphous                                      32 5,6-diF CF.sub.3 C.tbd.C-nPr  320.0691                                      33 5,6-diF CF.sub.3 C.tbd.C-Et  306.0550                                            (MH.sup.+)                                                                34 5,6-diF CF.sub.3 C.tbd.C-Me 217                                             35 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             324.1008                                         36 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2  324.1003                                            37 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2                                         CH.sub.2 CH.sub.3  310.0878                      38 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-cycPr 223-225 326.0639                   39 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-iPr 240 328.0797                         40 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-nPr 208-210                              41 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Et 230-232                               42 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.2 CH.sub.3                                            215-217 328.0800                                 43 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.3 207-208                                             314.0640                                         44 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                           199-200                                          45 6-OMe CF.sub.3 C.tbd.C-cycPr 155-157 312.0835                               46 6-OMe CF.sub.3 C.tbd.C-cycPr 143-144 312.0843                               47 6-OMe CF.sub.3 C.tbd.C-cycPr 142-144 312.0836                               48 6-OMe CF.sub.3 C.tbd.C-iPr 158-159 314.0998                                 49 6-OMe CF.sub.3 C.tbd.C-nPr 148-150 314.1007                                 50 6-OMe CF.sub.3 C.tbd.C-Me 177-180 286.0691                                  51 6-OMe CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.2 CH.sub.3 119-122 314.0989                                        52 6-OMe CF.sub.3 CH.sub.2 CH.sub.2                                           CH(CH.sub.3).sub.2  318                               (MH.sup.+)                                                                53 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3  304.1167                                               54 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                       352.1153                                         55 6-OMe,8-F CF.sub.3 C.tbd.C-cycPr 188-189 330.0738                           56 6-NMe.sub.2 CF.sub.3 C.tbd.C-cycPr  325.1173                                57 6-NMe.sub.2 CF.sub.3 C.tbd.C-iPr  327.1322                                  58 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                         331.1641                                         59 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2  331.1637                                        60 6-COCH.sub.3 CF.sub.3 C.tbd.C-Et                                           180-183                                          61 6-CH.sub.3 CF.sub.3 C.tbd.C-cycPr 189 296.0905                              62 6-CH.sub.3 CF.sub.3 C.tbd.C-Et 222 284.0882                                 63 6,8-diCl CF.sub.3 C.tbd.C-cycPr 152-153 348.9870                            64 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -Ph  389.0188                                (M.sup.+)                                                                 65 5,6,8-triF CF.sub.3 C.tbd.C-cycPr amorphous                                 66 5,6,8-triF CF.sub.3 C.tbd.C-iPr amorphous                                   67 5,6,8-triF CF.sub.3 C.tbd.C-nPr amorphous                                   68 5,6,8-triF CF.sub.3 C.tbd.C-Et amorphous                                    69 5,8-diF CF.sub.3 C.tbd.C-cycPr  335.0834                                         (M+NH.sub.4.sup.+)                                                        70 5,8-diF CF.sub.3 C.tbd.C-iPr  320.0710                                           (MH.sup.+)                                                                71 5,8-diF CF.sub.3 C.tbd.C-nPr  337.0970                                           (M+NH.sub.4.sup.+)                                                        72 5,8-diF CF.sub.3 C.tbd.C-Et  323.8817                                            (M+NH.sub.4.sup.+)                                                        73 6-iPr CF.sub.3 C.tbd.C-cycPr  324.1203                                      74 6-iPr CF.sub.3 C.tbd.C-iPr  326.1361                                        75 6-iPr CF.sub.3 C.tbd.C-Ph  360.1204                                         76 6-iPr CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                               330.1672                                         77 6-iPr CF.sub.3 CH.sub.2 CH.sub.2 -iPr  330.1673                             78 6-iPr CF.sub.3 CH.sub.2 CH.sub.2 -Ph  364.1517                              79 6-OCF.sub.3 CF.sub.3 C.tbd.C-cycPr  366.0561                                80 6-OCF.sub.3 CF.sub.3 C.tbd.C-iPr  368.0712                                  81 6-OCF.sub.3 CF.sub.3 C.tbd.C-Ph  401.0475                                   82 6-OCF.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                         372.1018                                         83 6-OCF.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -iPr  372.1039                       84 6-OCF.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -Ph  405.0795                        85 H CF.sub.3 CH.sub.2 CH.sub.2 -Ph  282.0735                                  86 H CF.sub.3 C.tbd.C-iPr  284.0894                                            87 H CF.sub.3 C.tbd.C-Ph  318.0748                                             88 H CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3  288.1201                                          89 H CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                          121-122                                          90 H CF.sub.3 CH.sub.2 CH.sub.2 -Ph  322.1055                                  91 6-Ph CF.sub.3 C.tbd.C-cycPr 185-186 358.1055                                92 6-Ph CF.sub.3 C.tbd.C-iPr 179-180 360.1211                                  93 6-Ph CF.sub.3 C.tbd.C-nPr 143-144 360.1211                                  94 6-Ph CF.sub.3 C.tbd.C-iBu 163-164 374.1352                                  95 6-Ph CF.sub.3 C.tbd.C-Et 195 346.1055                                       96 6-Ph CF.sub.3 CH.sub.2 CH.sub.2 -iPr 147-148 364.1524                       97 6-OMe iPr C.tbd.C-cycPr  286.1428                                           98 6-OMe iPr C.tbd.C-iPr  288.1583                                             99 6-CH.sub.3 cycPr C.tbd.C-iPr 133-134 270.1498                               100  6-CH.sub.3 iPr C.tbd.C-iPr 133-134 272.1648                               101  6-CH.sub.3 Et C.tbd.C-iPr 138-139 258.1505                                102  6-CH.sub.3 Et C.tbd.C-Et 138.5-139   244.1333                             103  6,7-diCl cycPr C.tbd.C-iPr                                                104  6,7-diCl iPr C.tbd.C-iPr amorphous                                        105  7-Cl cycPr C.tbd.C-cycPr  288.0783                                        106  7-Cl cycPr C.tbd.C-iPr  290.0941                                          107  7-Cl cycPr C.tbd.C-iBu 117-118 304.1110                                   108  7-Cl iPr C.tbd.C-cycPr  290.0940                                          109  7-Cl iPr C.tbd.-iPr  292.1103                                             110  6-Cl,8-aza CF.sub.3 C.tbd.C-cycPr  317.0317                               111  6-Cl,8-aza CF.sub.3 C.tbd.C-iPr  319                                           (MH.sup.+)                                                                112  6-Cl,8-aza CF.sub.3 CH.sub.2 CH.sub.2 -Ph 214-215 357.0625                                               113  6-OCH.sub.3,7- CF.sub.3 C.tbd.C-cycP                                     r 181-182 313.0800                                aza                                                                           114  6-aza CF.sub.3 C.tbd.C-cycPr                                            __________________________________________________________________________      *Unless otherwise noted, stereochemistry is (+/-)                        

                  TABLE 2                                                          ______________________________________                                           #STR43##                                                                       Ex. #      G            R.sup.1                                                                              R.sup.2                                        ______________________________________                                         201      6-Cl,8-F     CF.sub.3                                                                               C.tbd.C-iPr                                        202 6-Cl,8-F CF.sub.3 C.tbd.C-nPr                                              203 6-Cl,8-F CF.sub.3 C.tbd.C-Bu                                               204 6-Cl,8-F CF.sub.3 C.tbd.C-iBu                                              205 6-Cl,8-F CF.sub.3 C.tbd.C-tBu                                              206 6-Cl,8-F CF.sub.3 C.tbd.C-Me                                               207 6-Cl,8-F CF.sub.3 C.tbd.C-Ph                                               208 6-Cl,8-F CF.sub.3 C.tbd.C-(2-Cl)Ph                                         209 6-Cl,8-F CF.sub.3 C.tbd.C-(3-Cl)Ph                                         210 6-Cl,8-F CF.sub.3 C.tbd.C-(2-F)Ph                                          211 6-Cl,8-F CF.sub.3 C.tbd.C-(3-F)Ph                                          212 6-Cl,8-F CF.sub.3 C.tbd.C-(2-OH)Ph                                         213 6-Cl,8-F CF.sub.3 C.tbd.C-(3-OH)Ph                                         214 6-Cl,8-F CF.sub.3 C.tbd.C-(2-OMe)Ph                                        215 6-Cl,8-F CF.sub.3 C.tbd.C-(3-OMe)Ph                                        216 6-Cl,8-F CF.sub.3 C.tbd.C-(2-CN)Ph                                         217 6-Cl,8-F CF.sub.3 C.tbd.C-(3-CN)Ph                                         218 6-Cl,8-F CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                   219 6-Cl,8-F CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                   220 6-Cl,8-F CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                  221 6-Cl,8-F CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                  222 6-Cl,8-F CF.sub.3 C.tbd.C-2-Pyridyl                                        223 6-Cl,8-F CF.sub.3 C.tbd.C-3-Pyridyl                                        224 6-Cl,8-F CF.sub.3 C.tbd.C-4-Pyridyl                                        225 6-Cl,8-F CF.sub.3 C.tbd.C-2-furanyl                                        226 6-Cl,8-F CF.sub.3 C.tbd.C-3-furanyl                                        227 6-Cl,8-F CF.sub.3 C.tbd.C-2-thienyl                                        228 6-Cl,8-F CF.sub.3 C.tbd.C-3-thienyl                                        229 6-Cl,8-F CF.sub.3 CH═CH-cycPr                                          230 6-Cl,8-F CF.sub.3 CH═CH-iPr                                            231 6-Cl,8-F CF.sub.3 CH═CH-nPr                                            232 6-Cl,8-F CF.sub.3 CH═CH-Bu                                             233 6-Cl,8-F CF.sub.3 CH═CH-iBu                                            234 6-Cl,8-F CF.sub.3 CH═CH-tBu                                            235 6-Cl,8-F CF.sub.3 CH═CH-Et                                             236 6-Cl,8-F CF.sub.3 CH═CH-Me                                             237 6-Cl,8-F CF.sub.3 CH═CH-Ph                                             238 6-Cl,8-F CF.sub.3 CH═CH-2-Pyridyl                                      239 6-Cl,8-F CF.sub.3 CH═CH-3-Pyridyl                                      240 6-Cl,8-F CF.sub.3 CH═CH-4-Pyridyl                                      241 6-Cl,8-F CF.sub.3 CH═CH-2-furanyl                                      242 6-Cl,8-F CF.sub.3 CH═CH-3-furanyl                                      243 6-Cl,8-F CF.sub.3 CH═CH-2-thienyl                                      244 6-Cl,8-F CF.sub.3 CH═CH-3-thienyl                                      245 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                          246 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2                                       CH.sub.2 CH.sub.3                                  247 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                 248 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                   249 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                    250 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                             251 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                             252 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                             253 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                             254 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                             255 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                             256 6-Cl,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                             257 5,6-diF CF.sub.3 C.tbd.C-Bu                                                258 5,6-diF CF.sub.3 C.tbd.C-iBu                                               259 5,6-diF CF.sub.3 C.tbd.C-tBu                                               260 5,6-diF CF.sub.3 C.tbd.CH.sub.2 CH.sub.2 OH                                261 5,6-diF CF.sub.3 C.tbd.C--CH(OH)Me                                         262 5,6-diF CF.sub.3 C.tbd.C-Ph                                                263 5,6-diF CF.sub.3 C.tbd.C-(2-Cl)Ph                                          264 5,6-diF CF.sub.3 C.tbd.C-(3-Cl)Ph                                          265 5,6-diF CF.sub.3 C.tbd.C-(4-Cl)Ph                                          266 5,6-diF CF.sub.3 C.tbd.C-(2-F)Ph                                           267 5,6-diF CF.sub.3 C.tbd.C-(3-F)Ph                                           268 5,6-diF CF.sub.3 C.tbd.C-(4-F)Ph                                           269 5,6-diF CF.sub.3 C.tbd.C-(2-OH)Ph                                          270 5,6-diF CF.sub.3 C.tbd.C-(3-OH)Ph                                          271 5,6-diF CF.sub.3 C.tbd.C-(4-OH)Ph                                          272 5,6-diF CF.sub.3 C.tbd.C-(2-OMe)Ph                                         273 5,6-diF CF.sub.3 C.tbd.C-(3-OMe)Ph                                         274 5,6-diF CF.sub.3 C.tbd.C-(4-OMe)Ph                                         275 5,6-diF CF.sub.3 C.tbd.C-(2-CN)Ph                                          276 5,6-diF CF.sub.3 C.tbd.C-(3-CN)Ph                                          277 5,6-diF CF.sub.3 C.tbd.C-(4-CN)Ph                                          278 5,6-diF CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                    279 5,6-diF CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                    280 5,6-diF CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                    281 5,6-diF CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                    282 5,6-diF CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                    283 5,6-diF CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                    284 5,6-diF CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                   285 5,6-diF CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                   286 5,6-diF CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                   287 5,6-diF CF.sub.3 C.tbd.C-2-Pyridyl                                         288 5,6-diF CF.sub.3 C.tbd.C-3-Pyridyl                                         289 5,6-diF CF.sub.3 C.tbd.C-4-Pyridyl                                         290 5,6-diF CF.sub.3 C.tbd.C-2-furanyl                                         291 5,6-diF CF.sub.3 C.tbd.C-3-furanyl                                         292 5,6-diF CF.sub.3 C.tbd.C-2-thienyl                                         293 5,6-diF CF.sub.3 C.tbd.C-3-thienyl                                         294 5,6-diF CF.sub.3 C.tbd.C-2-oxazolyl                                        295 5,6-diF CF.sub.3 C.tbd.C-2-thiazolyl                                       296 5,6-diF CF.sub.3 C.tbd.C-4-isoxazolyl                                      297 5,6-diF CF.sub.3 C.tbd.C-2-imidazolyl                                      298 5,6-diF CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.3                                299 5,6-diF CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.2 CH.sub.3                       300 5,6-diF CF.sub.3 CH═CH-cycPr                                           301 5,6-diF CF.sub.3 CH═CH-iPr                                             302 5,6-diF CF.sub.3 CH═CH-nPr                                             303 5,6-diF CF.sub.3 CH═CH-Bu                                              304 5,6-diF CF.sub.3 CH═CH-iBu                                             305 5,6-diF CF.sub.3 CH═CH-tBu                                             306 5,6-diF CF.sub.3 CH═CH-Et                                              307 5,6-diF CF.sub.3 CH═CH-Me                                              308 5,6-diF CF.sub.3 CH═CH-Ph                                              309 5,6-diF CF.sub.3 CH═CH-2-Pyridyl                                       310 5,6-diF CF.sub.3 CH═CH-3-Pyridyl                                       311 5,6-diF CF.sub.3 CH═CH-4-Pyridyl                                       312 5,6-diF CF.sub.3 CH═CH-2-furanyl                                       313 5,6-diF CF.sub.3 CH═CH-3-furanyl                                       314 5,6-diF CF.sub.3 CH═CH-2-thienyl                                       315 5,6-diF CF.sub.3 CH═CH-3-thienyl                                       316 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                                317 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                  318 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                    319 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                    320 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                              321 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 Ph                                      322 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-Cl)Ph                               323 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-Cl)Ph                               324 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-Cl)Ph                               325 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-F)Ph                                326 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-F)Ph                                327 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-F)Ph                                328 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-OH)Ph                               329 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-OH)Ph                               330 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-OH)Ph                               331 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-OMe)Ph                              332 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-OMe)Ph                              333 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-OMe)Ph                              334 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-CN)Ph                               335 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-CN)Ph                               336 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-CN)Ph                               337 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-NO.sub.2)Ph                         338 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-NO.sub.2)Ph                         339 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-NO.sub.2)Ph                         340 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-NH.sub.2)Ph                         341 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-NH.sub.2)Ph                         342 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-NH.sub.2)Ph                         343 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(2-NMe.sub.2)Ph                        344 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(3-NMe.sub.2)Ph                        345 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -(4-NMe.sub.2)Ph                        346 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                              347 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                              348 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                              349 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                              350 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                              351 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                              352 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                              353 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-oxazolyl                             354 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-thiazolyl                            355 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -4-isoxazolyl                           356 5,6-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-imidazolyl                           357 5,6-diCl CF.sub.3 C.tbd.C-cycPr                                            358 5,6-diCl CF.sub.3 C.tbd.C-iPr                                              359 5,6-diCl CF.sub.3 C.tbd.C-nPr                                              360 5,6-diCl CF.sub.3 C.tbd.C-Bu                                               361 5,6-diCl CF.sub.3 C.tbd.C-iBu                                              362 5,6-diCl CF.sub.3 C.tbd.C-tBu                                              363 5,6-diCl CF.sub.3 C.tbd.C-Et                                               364 5,6-diCl CF.sub.3 C.tbd.C-Me                                               365 5,6-diCl CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                              366 5,6-diCl CF.sub.3 C.tbd.C--CH(OH)Me                                        367 5,6-diCl CF.sub.3 C.tbd.C-Ph                                               368 5,6-diCl CF.sub.3 C.tbd.C-(2-Cl)Ph                                         369 5,6-diCl CF.sub.3 C.tbd.C-(3-Cl)Ph                                         370 5,6-diCl CF.sub.3 C.tbd.C-(4-Cl)Ph                                         371 5,6-diCl CF.sub.3 C.tbd.C-(2-F)Ph                                          372 5,6-diCl CF.sub.3 C.tbd.C-(3-F)Ph                                          373 5,6-diCl CF.sub.3 C.tbd.C-(4-F)Ph                                          374 5,6-diCl CF.sub.3 C.tbd.C-(2-OH)Ph                                         375 5,6-diCl CF.sub.3 C.tbd.C-(3-OH)Ph                                         376 5,6-diCl CF.sub.3 C.tbd.C-(4-OH)Ph                                         377 5,6-diCl CF.sub.3 C.tbd.C-(2-OMe)Ph                                        378 5,6-diCl CF.sub.3 C.tbd.C-(3-OMe)Ph                                        379 5,6-diCl CF.sub.3 C.tbd.C-(4-OMe)Ph                                        380 5,6-diCl CF.sub.3 C.tbd.C-(2-CN)Ph                                         381 5,6-diCl CF.sub.3 C.tbd.C-(3-CN)Ph                                         382 5,6-diCl CF.sub.3 C.tbd.C-(4-CN)Ph                                         383 5,6-diCl CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                   384 5,6-diCl CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                   385 5,6-diCl CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                   386 5,6-diCl CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                   387 5,6-diCl CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                   388 5,6-diCl CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                   389 5,6-diCl CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                  390 5,6-diCl CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                  391 5,6-diCl CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                  392 5,6-diCl CF.sub.3 C.tbd.C-2-Pyridyl                                        393 5,6-diCl CF.sub.3 C.tbd.C-3-Pyridyl                                        394 5,6-diCl CF.sub.3 C.tbd.C-4-Pyridyl                                        395 5,6-diCl CF.sub.3 C.tbd.C-2-furanyl                                        396 5,6-diCl CF.sub.3 C.tbd.C-3-furanyl                                        397 5,6-diCl CF.sub.3 C.tbd.C-2-thienyl                                        398 5,6-diCl CF.sub.3 C.tbd.C-3-thienyl                                        399 5,6-diCl CF.sub.3 CH═CH-cycPr                                          400 5,6-diCl CF.sub.3 CH═CH-iPr                                            401 5,6-diCl CF.sub.3 CH═CH-nPr                                            402 5,6-diCl CF.sub.3 CH═CH-Bu                                             403 5,6-diCl CF.sub.3 CH═CH-iBu                                            404 5,6-diCl CF.sub.3 CH═CH-tBu                                            405 5,6-diCl CF.sub.3 CH═CH-Et                                             406 5,6-diCl CF.sub.3 CH═CH-Me                                             407 5,6-diCl CF.sub.3 CH═CH-Ph                                             408 5,6-diCl CF.sub.3 CH═CH-2-Pyridyl                                      409 5,6-diCl CF.sub.3 CH═CH-3-Pyridyl                                      410 5,6-diCl CF.sub.3 CH═CH-4-Pyridyl                                      411 5,6-diCl CF.sub.3 CH═CH-2-furanyl                                      412 5,6-diCl CF.sub.3 CH═CH-3-furanyl                                      413 5,6-diCl CF.sub.3 CH═CH-2-thienyl                                      414 5,6-diCl CF.sub.3 CH═CH-3-thienyl                                      415 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                          416 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2                                       CH(CH.sub.3).sub.2                                 417 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                      418 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                 419 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                   420 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                   421 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                             422 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                    423 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                             424 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                             425 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                             426 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                             427 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                             428 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                             429 5,6-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                             430 5-Cl,6-F CF.sub.3 C.tbd.C-cycPr                                            431 5-Cl,6-F CF.sub.3 C.tbd.C-iPr                                              432 5-Cl,6-F CF.sub.3 C.tbd.C-nPr                                              433 5-Cl,6-F CF.sub.3 C.tbd.C-Bu                                               434 5-Cl,6-F CF.sub.3 C.tbd.C-iBu                                              435 5-Cl,6-F CF.sub.3 C.tbd.C-tBu                                              436 5-Cl,6-F CF.sub.3 C.tbd.C-Et                                               437 5-Cl,6-F CF.sub.3 C.tbd.C-Me                                               438 5-Cl,6-F CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                              439 5-Cl,6-F CF.sub.3 C.tbd.C--CH(OH)Me                                        440 5-Cl,6-F CF.sub.3 C.tbd.C-Ph                                               441 5-Cl,6-F CF.sub.3 C.tbd.C-(2-Cl)Ph                                         442 5-Cl,6-F CF.sub.3 C.tbd.C-(3-Cl)Ph                                         443 5-Cl,6-F CF.sub.3 C.tbd.C-(4-Cl)Ph                                         444 5-Cl,6-F CF.sub.3 C.tbd.C-(2-F)Ph                                          445 5-Cl,6-F CF.sub.3 C.tbd.C-(3-F)Ph                                          446 5-Cl,6-F CF.sub.3 C.tbd.C-(4-F)Ph                                          447 5-Cl,6-F CF.sub.3 C.tbd.C-(2-OH)Ph                                         448 5-Cl,6-F CF.sub.3 C.tbd.C-(3-OH)Ph                                         449 5-Cl,6-F CF.sub.3 C.tbd.C-(4-OH)Ph                                         450 5-Cl,6-F CF.sub.3 C.tbd.C-(2-OMe)Ph                                        451 5-Cl,6-F CF.sub.3 C.tbd.C-(3-OMe)Ph                                        452 5-Cl,6-F CF.sub.3 C.tbd.C-(4-OMe)Ph                                        453 5-Cl,6-F CF.sub.3 C.tbd.C-(2-CN)Ph                                         454 5-Cl,6-F CF.sub.3 C.tbd.C-(3-CN)Ph                                         455 5-Cl,6-F CF.sub.3 C.tbd.C-(4-CN)Ph                                         456 5-Cl,6-F CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                   457 5-Cl,6-F CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                   458 5-Cl,6-F CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                   459 5-Cl,6-F CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                   460 5-Cl,6-F CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                   461 5-Cl,6-F CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                   462 5-Cl,6-F CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                  463 5-Cl,6-F CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                  464 5-Cl,6-F CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                  465 5-Cl,6-F CF.sub.3 C.tbd.C-2-Pyridyl                                        466 5-Cl,6-F CF.sub.3 C.tbd.C-3-Pyridyl                                        467 5-Cl,6-F CF.sub.3 C.tbd.C-4-Pyridyl                                        468 5-Cl,6-F CF.sub.3 C.tbd.C-2-furanyl                                        469 5-Cl,6-F CF.sub.3 C.tbd.C-3-furanyl                                        470 5-Cl,6-F CF.sub.3 C.tbd.C-2-thienyl                                        471 5-Cl,6-F CF.sub.3 C.tbd.C-3-thienyl                                        472 5-Cl,6-F CF.sub.3 CH═CH-cycPr                                          473 5-Cl,6-F CF.sub.3 CH═CH-iPr                                            474 5-Cl,6-F CF.sub.3 CH═CH-nPr                                            475 5-Cl,6-F CF.sub.3 CH═CH-Bu                                             476 5-Cl,6-F CF.sub.3 CH═CH-iBu                                            477 5-Cl,6-F CF.sub.3 CH═CH-tBu                                            478 5-Cl,6-F CF.sub.3 CH═CH-Et                                             479 5-Cl,6-F CF.sub.3 CH═CH-Me                                             480 5-Cl,6-F CF.sub.3 CH═CH-Ph                                             481 5-Cl,6-F CF.sub.3 CH═CH-2-Pyridyl                                      482 5-Cl,6-F CF.sub.3 CH═CH-3-Pyridyl                                      483 5-Cl,6-F CF.sub.3 CH═CH-4-Pyridyl                                      484 5-Cl,6-F CF.sub.3 CH═CH-2-furanyl                                      485 5-Cl,6-F CF.sub.3 CH═CH-3-furanyl                                      486 5-Cl,6-F CF.sub.3 CH═CH-2-thienyl                                      487 5-Cl,6-F CF.sub.3 CH═CH-3-thienyl                                      488 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                          489 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2                                       CH(CH.sub.3).sub.2                                 490 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                      491 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                 492 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                   493 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                   494 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                             495 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                    496 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                             497 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                             498 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                             499 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                             500 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                             501 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                             502 5-Cl,6-F CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                             503 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Bu                                      504 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-iBu                                     505 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-tBu                                     506 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Me                                      507 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                     508 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C--CH(OH)Me                               509 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Ph                                      510 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-Cl)Ph                                511 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-Cl)Ph                                512 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-Cl)Ph                                513 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-F)Ph                                 514 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-F)Ph                                 515 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-F)Ph                                 516 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-OH)Ph                                517 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-OH)Ph                                518 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-OH)Ph                                519 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-OMe)Ph                               520 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-OMe)Ph                               521 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-OMe)Ph                               522 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-CN)Ph                                523 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-CN)Ph                                524 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-CN)Ph                                525 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                          526 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                          527 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                          528 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                          529 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                          530 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-NH2)Ph                               531 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                         532 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                         533 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                         534 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-Pyridyl                               535 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-Pyridyl                               536 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-4-Pyridyl                               537 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-furanyl                               538 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-furanyl                               539 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-thienyl                               540 5,6-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-thienyl                               541 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-cycPr                                 542 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-iPr                                   543 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-nPr                                   544 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-Bu                                    545 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-iBu                                   546 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-tBu                                   547 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-Et                                    548 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-Me                                    549 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-Ph                                    550 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-2-Pyridyl                             551 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-3-Pyridyl                             552 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-4-Pyridyl                             553 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-2-furanyl                             554 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-3-furanyl                             555 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-2-thienyl                             556 5,6-OCH.sub.2 O-- CF.sub.3 CH═CH-3-thienyl                             557 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                         CH.sub.3                                           558 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                          559 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2                                       CH.sub.2 -cycPr                                    560 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -tBu                          561 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                                       562 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2                                       CH.sub.2 --CH(OH)Me                                563 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -Ph                           564 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                    565 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                    566 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                    567 5;6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                    568 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                    569 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                    570 5,6-OCH.sub.2 O-- CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                    571 5-F CF.sub.3 C.tbd.C-cycPr                                                 572 5-F CF.sub.3 C.tbd.C-iPr                                                   573 5-F CF.sub.3 C.tbd.C-nPr                                                   574 5-F CF.sub.3 C.tbd.C-Bu                                                    575 5-F CF.sub.3 C.tbd.C-iBu                                                   576 5-F CF.sub.3 C.tbd.C-tBu                                                   577 5-F CF.sub.3 C.tbd.C-Et                                                    578 5-F CF.sub.3 C.tbd.C-Me                                                    579 5-F CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                                   580 5-F CF.sub.3 C.tbd.C--CH(OH)Me                                             581 5-F CF.sub.3 C.tbd.C-Ph                                                    582 5-F CF.sub.3 C.tbd.C-(2-Cl)Ph                                              583 5-F CF.sub.3 C.tbd.C-(3-Cl)Ph                                              584 5-F CF.sub.3 C.tbd.C-(4-Cl)Ph                                              585 5-F CF.sub.3 C.tbd.C-(2-F)Ph                                               586 5-F CF.sub.3 C.tbd.C-(3-F)Ph                                               587 5-F CF.sub.3 C.tbd.C-(4-F)Ph                                               588 5-F CF.sub.3 C.tbd.C-(2-OH)Ph                                              589 5-F CF.sub.3 C.tbd.C-(3-OH)Ph                                              590 5-F CF.sub.3 C.tbd.C-(4-OH)Ph                                              591 5-F CF.sub.3 C.tbd.C-(2-OMe)Ph                                             592 5-F CF.sub.3 C.tbd.C-(3-OMe)Ph                                             593 5-F CF.sub.3 C.tbd.C-(4-OMe)Ph                                             594 5-F CF.sub.3 C.tbd.C-(2-CN)Ph                                              595 5-F CF.sub.3 C.tbd.C-(3-CN)Ph                                              596 5-F CF.sub.3 C.tbd.C-(4-CN)Ph                                              597 5-F CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                        598 5-F CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                        599 5-F CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                        600 5-F CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                        601 5-F CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                        602 5-F CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                        603 5-F CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                       604 5-F CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                       605 5-F CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                       606 5-F CF.sub.3 C.tbd.C-2-Pyridyl                                             607 5-F CF.sub.3 C.tbd.C-3-Pyridyl                                             608 5-F CF.sub.3 C.tbd.C-4-Pyridyl                                             609 5-F CF.sub.3 C.tbd.C-2-furanyl                                             610 5-F CF.sub.3 C.tbd.C-3-furanyl                                             611 5-F CF.sub.3 C.tbd.C-2-thienyl                                             612 5-F CF.sub.3 C.tbd.C-3-thienyl                                             613 5-F CF.sub.3 CH═CH-cycPr                                               614 5-F CF.sub.3 CH═CH-iPr                                                 615 5-F CF.sub.3 CH═CH-nPr                                                 616 5-F CF.sub.3 CH═CH-Bu                                                  617 5-F CF.sub.3 CH═CH-iBu                                                 618 5-F CF.sub.3 CH═CH-tBu                                                 619 5-F CF.sub.3 CH═CH-Et                                                  620 5-F CF.sub.3 CH═CH-Me                                                  621 5-F CF.sub.3 CH═CH-Ph                                                  622 5-F CF.sub.3 CH═CH-2-Pyridyl                                           623 5-F CF.sub.3 CH═CH-3-Pyridyl                                           624 5-F CF.sub.3 CH═CH-4-Pyridyl                                           625 5-F CF.sub.3 CH═CH-2-furanyl                                           626 5-F CF.sub.3 CH═CH-3-furanyl                                           627 5-F CF.sub.3 CH═CH-2-thienyl                                           628 5-F CF.sub.3 CH═CH-3-thienyl                                           629 5-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  630 5-F CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                          631 5-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                           632 5-F CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                      633 5-F CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                        634 5-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                        635 5-F CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                                  636 5-F CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                         637 5-F CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                  638 5-F CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                                  639 5-F CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                                  640 5-F CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                                  641 5-F CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                                  642 5-F CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                                  643 5-F CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                                  644 5-Cl CF.sub.3 C.tbd.C-cycPr                                                645 5-Cl CF.sub.3 C.tbd.C-iPr                                                  646 5-Cl CF.sub.3 C.tbd.C-nPr                                                  647 5-Cl CF.sub.3 C.tbd.C-Bu                                                   648 5-Cl CF.sub.3 C.tbd.C-iBu                                                  649 5-Cl CF.sub.3 C.tbd.C-tBu                                                  650 5-Cl CF.sub.3 C.tbd.C-Et                                                   651 5-Cl CF.sub.3 C.tbd.C-Me                                                   652 5-Cl CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                                  653 5-Cl CF.sub.3 C.tbd.C--CH(OH)Me                                            654 5-Cl CF.sub.3 C.tbd.C-Ph                                                   655 5-Cl CF.sub.3 C.tbd.C-(2-Cl)Ph                                             656 5-Cl CF.sub.3 C.tbd.C-(3-Cl)Ph                                             657 5-Cl CF.sub.3 C.tbd.C-(4-Cl)Ph                                             658 5-Cl CF.sub.3 C.tbd.C-(2-F)Ph                                              659 5-Cl CF.sub.3 C.tbd.C-(3-F)Ph                                              660 5-Cl CF.sub.3 C.tbd.C-(4-F)Ph                                              661 5-Cl CF.sub.3 C.tbd.C-(2-OH)Ph                                             662 5-Cl CF.sub.3 C.tbd.C-(3-OH)Ph                                             663 5-Cl CF.sub.3 C.tbd.C-(4-OH)Ph                                             664 5-Cl CF.sub.3 C.tbd.C-(2-OMe)Ph                                            665 5-Cl CF.sub.3 C.tbd.C-(3-OMe)Ph                                            666 5-Cl CF.sub.3 C.tbd.C-(4-OMe)Ph                                            667 5-Cl CF.sub.3 C.tbd.C-(2-CN)Ph                                             668 5-Cl CF.sub.3 C.tbd.C-(3-CN)Ph                                             669 5-Cl CF.sub.3 C.tbd.C-(4-CN)Ph                                             670 5-Cl CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                       671 5-Cl CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                       672 5-Cl CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                       673 5-Cl CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                       674 5-Cl CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                       675 5-Cl CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                       676 5-Cl CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                      677 5-Cl CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                      678 5-Cl CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                      679 5-Cl CF.sub.3 C.tbd.C-2-Pyridyl                                            680 5-Cl CF.sub.3 C.tbd.C-3-Pyridyl                                            681 5-Cl CF.sub.3 C.tbd.C-4-Pyridyl                                            682 5-Cl CF.sub.3 C.tbd.C-2-furanyl                                            683 5-Cl CF.sub.3 C.tbd.C-3-furanyl                                            684 5-Cl CF.sub.3 C.tbd.C-2-thienyl                                            685 5-Cl CF.sub.3 C.tbd.C-3-thienyl                                            686 5-Cl CF.sub.3 CH═CH-cycPr                                              687 5-Cl CF.sub.3 CH═CH-iPr                                                688 5-Cl CF.sub.3 CH═CH-nPr                                                689 5-Cl CF.sub.3 CH═CH-Bu                                                 690 5-Cl CF.sub.3 CH═CH-iBu                                                691 5-Cl CF.sub.3 CH═CH-tBu                                                692 5-Cl CF.sub.3 CH═CH-Et                                                 693 5-Cl CF.sub.3 CH═CH-Me                                                 694 5-Cl CF.sub.3 CH═CH-Ph                                                 695 5-Cl CF.sub.3 CH═CH-2-Pyridyl                                          696 5-Cl CF.sub.3 CH═CH-3-Pyridyl                                          697 5-Cl CF.sub.3 CH═CH-4-Pyridyl                                          698 5-Cl CF.sub.3 CH═CH-2-furanyl                                          699 5-Cl CF.sub.3 CH═CH-3-furanyl                                          700 5-Cl CF.sub.3 CH═CH-2-thienyl                                          701 5-Cl CF.sub.3 CH═CH-3-thienyl                                          702 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                 703 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                         704 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                          705 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                     706 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                       707 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                       708 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                                 709 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                        710 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                 711 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                                 712 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                                 713 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                                 714 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                                 715 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                                 716 5-Cl CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                                 717 6-OMe CF.sub.3 C.tbd.C-Bu                                                  718 6-OMe CF.sub.3 C.tbd.C-iBu                                                 719 6-OMe CF.sub.3 C.tbd.C-tBu                                                 720 6-OMe CF.sub.3 C.tbd.CCH.sub.2 CH.sub.2 OH                                 721 6-OMe CF.sub.3 C.tbd.C--CH(OH)Me                                           722 6-OMe CF.sub.3 C.tbd.C-Ph                                                  723 6-OMe CF.sub.3 C.tbd.C-(2-Cl)Ph                                            724 6-OMe CF.sub.3 C.tbd.C-(3-Cl)Ph                                            725 6-OMe CF.sub.3 C.tbd.C-(4-Cl)Ph                                            726 6-OMe CF.sub.3 C.tbd.C-(2-F)Ph                                             727 6-OMe CF.sub.3 C.tbd.C-(3-F)Ph                                             728 6-OMe CF.sub.3 C.tbd.C-(4-F)Ph                                             729 6-OMe CF.sub.3 C.tbd.C-(2-OH)Ph                                            730 6-OMe CF.sub.3 C.tbd.C-(3-OH)Ph                                            731 6-OMe CF.sub.3 C.tbd.C-(4-OH)Ph                                            732 6-OMe CF.sub.3 C.tbd.C-(2-OMe)Ph                                           733 6-OMe CF.sub.3 C.tbd.C-(3-OMe)Ph                                           734 6-OMe CF.sub.3 C.tbd.C-(4-OMe)Ph                                           735 6-OMe CF.sub.3 C.tbd.C-(2-CN)Ph                                            736 6-OMe CF.sub.3 C.tbd.C-(3-CN)Ph                                            737 6-OMe CF.sub.3 C.tbd.C-(4-CN)Ph                                            738 6-OMe CF.sub.3 C.tbd.C-(2-NO.sub.2)Ph                                      739 6-OMe CF.sub.3 C.tbd.C-(3-NO.sub.2)Ph                                      740 6-OMe CF.sub.3 C.tbd.C-(4-NO.sub.2)Ph                                      741 6-OMe CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                      742 6-OMe CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                      743 6-OMe CF.sub.3 C.tbd.C-(4-NH.sub.2)Ph                                      744 6-OMe CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                     745 6-OMe CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                     746 6-OMe CF.sub.3 C.tbd.C-(4-NMe.sub.2)Ph                                     747 6-OMe CF.sub.3 C.tbd.C-2-Pyridyl                                           748 6-OMe CF.sub.3 C.tbd.C-3-Pyridyl                                           749 6-OMe CF.sub.3 C.tbd.C-4-Pyridyl                                           750 6-OMe CF.sub.3 C.tbd.C-2-furanyl                                           751 6-OMe CF.sub.3 C.tbd.C-3-furanyl                                           752 6-OMe CF.sub.3 C.tbd.C-2-thienyl                                           753 6-OMe CF.sub.3 C.tbd.C-3-thienyl                                           754 6-OMe CF.sub.3 C.tbd.C-2-oxazolyl                                          755 6-OMe CF.sub.3 C.tbd.C-2-thiazolyl                                         756 6-OMe CF.sub.3 C.tbd.C-4-isoxazolyl                                        757 6-OMe CF.sub.3 C.tbd.C-2-imidazolyl                                        758 6-OMe CF.sub.3 CH.sub.2 C.tbd.C--CH.sub.3                                  759 6-OMe CF.sub.3 CH═CH-cycPr                                             760 6-OMe CF.sub.3 CH═CH-iPr                                               761 6-OMe CF.sub.3 CH═CH-nPr                                               762 6-OMe CF.sub.3 CH═CH-Bu                                                763 6-OMe CF.sub.3 CH═CH-iBu                                               764 6-OMe CF.sub.3 CH═CH-tBu                                               765 6-OMe CF.sub.3 CH═CH-Et                                                766 6-OMe CF.sub.3 CH═CH-Me                                                767 6-OMe CF.sub.3 CH═CH-Ph                                                768 6-OMe CF.sub.3 CH═CH-2-Pyridyl                                         769 6-OMe CF.sub.3 CH═CH-3-Pyridyl                                         770 6-OMe CF.sub.3 CH═CH-4-Pyridyl                                         771 6-OMe CF.sub.3 CH═CH-2-furanyl                                         772 6-OMe CF.sub.3 CH═CH-3-furanyl                                         773 6-OMe CF.sub.3 CH═CH-2-thienyl                                         774 6-OMe CF.sub.3 CH═CH-3-thienyl                                         775 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             776 6-OMe CF.sub.3 CH.sub.2 CH.sub.2                                          CH.sub.3                                           777 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                    778 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                      779 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 OH                      780 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 --CH(OH)Me                                781 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-Cl)Ph                                 782 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-Cl)Ph                                 783 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-Cl)Ph                                 784 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-F)Ph                                  785 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-F)Ph                                  786 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-F)Ph                                  787 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-OH)Ph                                 788 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-OH)Ph                                 789 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-OH)Ph                                 790 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-OMe)Ph                                791 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-OMe)Ph                                792 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-OMe)Ph                                793 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-CN)Ph                                 794 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-CN)Ph                                 795 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-CN)Ph                                 796 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-NO.sub.2)Ph                           797 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-NO.sub.2)Ph                           798 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-NO.sub.2)Ph                           799 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-NH.sub.2)Ph                           800 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-NH.sub.2)Ph                           801 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-NH.sub.2)Ph                           802 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(2-NMe.sub.2)Ph                          803 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(3-NMe.sub.2)Ph                          804 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -(4-NMe.sub.2)Ph                          805 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                806 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                                807 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                                808 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                                809 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                                810 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                                811 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                                812 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-oxazolyl                               813 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-thiazolyl                              814 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -4-isoxazolyl                             815 6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-imidazolyl                             816 6-OMe,8-F CF.sub.3 C.tbd.C-iPr                                             817 6-OMe,8-F CF.sub.3 C.tbd.C-nPr                                             818 6-OMe,8-F CF.sub.3 C.tbd.C-Et                                              819 6-OMe,8-F CF.sub.3 C.tbd.C-Me                                              820 6-OMe,8-F CF.sub.3 C.tbd.C-Ph                                              821 6-OMe,8-F CF.sub.3 C.tbd.C-2-Pyridyl                                       822 6-OMe,8-F CF.sub.3 C.tbd.C-3-Pyridyl                                       823 6-OMe,8-F CF.sub.3 C.tbd.C-4-Pyridyl                                       824 6-OMe,8-F CF.sub.3 C.tbd.C-2-furanyl                                       825 6-OMe,8-F CF.sub.3 C.tbd.C-3-furanyl                                       826 6-OMe,8-F CF.sub.3 C.tbd.C-2-thienyl                                       827 6-OMe,8-F CF.sub.3 C.tbd.C-3-thienyl                                       828 6-OMe,8-F CF.sub.3 CH═CH-cycPr                                         829 6-OMe,8-F CF.sub.3 CH═CH-iPr                                           830 6-OMe,8-F CF.sub.3 CH═CH-nPr                                           831 6-OMe,8-F CF.sub.3 CH═CH-Et                                            832 6-OMe,8-F CF.sub.3 CH═CH-Me                                            833 6-OMe,8-F CF.sub.3 CH═CH-Ph                                            834 6-OMe,8-F CF.sub.3 CH═CH-2-Pyridyl                                     835 6-OMe,8-F CF.sub.3 CH═CH-3-Pyridyl                                     836 6-OMe,8-F CF.sub.3 CH═CH-4-Pyridyl                                     837 6-OMe,8-F CF.sub.3 CH═CH-2-furanyl                                     838 6-OMe,8-F CF.sub.3 CH═CH-3-furanyl                                     839 6-OMe,8-F CF.sub.3 CH═CH-2-thienyl                                     840 6-OMe,8-F CF.sub.3 CH═CH-3-thienyl                                     841 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                         842 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2                                      CH(CH.sub.3).sub.2                                 843 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                     844 6-OMe,8-F CF.sub.3 CH.sub.2 CH-cycPr                                       845 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                   846 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                            847 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                            848 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                            849 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                            850 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                            851 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                            852 6-OMe,8-F CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                            853 5-F,6-OMe CF.sub.3 C.tbd.C-cycPr                                           854 5-F,6-OMe CF.sub.3 C.tbd.C-iPr                                             855 5-F,6-OMe CF.sub.3 C.tbd.C-nPr                                             856 5-F,6-OMe CF.sub.3 C.tbd.C-Bu                                              857 5-F,6-OMe CF.sub.3 C.tbd.C-iBu                                             858 5-F,6-OMe CF.sub.3 C.tbd.C-tBu                                             859 5-F,6-OMe CF.sub.3 C.tbd.C-Et                                              860 5-F,6-OMe CF.sub.3 C.tbd.C-Me                                              861 5-F,6-OMe CF.sub.3 C.tbd.C-Ph                                              862 5-F,6-OMe CF.sub.3 C.tbd.C-(2-Cl)Ph                                        863 5-F,6-OMe CF.sub.3 C.tbd.C-(3-Cl)Ph                                        864 5-F,6-OMe CF.sub.3 C.tbd.C-(2-F)Ph                                         865 5-F,6-OMe CF.sub.3 C.tbd.C-(3-F)Ph                                         866 5-F,6-OMe CF.sub.3 C.tbd.C-(2-OH)Ph                                        867 5-F,6-OMe CF.sub.3 C.tbd.C-(3-OH)Ph                                        868 5-F,6-OMe CF.sub.3 C.tbd.C-(2-OMe)Ph                                       869 5-F,6-OMe CF.sub.3 C.tbd.C-(3-OMe)Ph                                       870 5-F,6-OMe CF.sub.3 C.tbd.C-(2-CN)Ph                                        871 5-F,6-OMe CF.sub.3 C.tbd.C-(3-CN)Ph                                        872 5-F,6-OMe CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                  873 5-F,6-OMe CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                  874 5-F,6-OMe CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                                 875 5-F,6-OMe CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                                 876 5-F,6-OMe CF.sub.3 C.tbd.C-2-Pyridyl                                       877 5-F,6-OMe CF.sub.3 C.tbd.C-3-Pyridyl                                       878 5-F,6-OMe CF.sub.3 C.tbd.C-4-Pyridyl                                       879 5-F,6-OMe CF.sub.3 C.tbd.C-2-furanyl                                       880 5-F,6-OMe CF.sub.3 C.tbd.C-3-furanyl                                       881 5-F,6-OMe CF.sub.3 C.tbd.C-2-thienyl                                       882 5-F,6-OMe CF.sub.3 C.tbd.C-3-thienyl                                       883 5-F,6-OMe CF.sub.3 CH═CH-cycPr                                         884 5-F,6-OMe CF.sub.3 CH═CH-iPr                                           885 5-F,6-OMe CF.sub.3 CH═CH-nPr                                           886 5-F,6-OMe CF.sub.3 CH═CH-Bu                                            887 5-F,6-OMe CF.sub.3 CH═CH-iBu                                           888 5-F,6-OMe CF.sub.3 CH═CH-tBu                                           889 5-F,6-OMe CF.sub.3 CH═CH-Et                                            890 5-F,6-OMe CF.sub.3 CH═CH-Me                                            891 5-F,6-OMe CF.sub.3 CH═CH-Ph                                            892 5-F,6-OMe CF.sub.3 CH═CH-2-Pyridyl                                     893 5-F,6-OMe CF.sub.3 CH═CH-3-Pyridyl                                     894 5-F,6-OMe CF.sub.3 CH═CH-4-Pyridyl                                     895 5-F,6-OMe CF.sub.3 CH═CH-2-furanyl                                     896 5-F,6-OMe CF.sub.3 CH═CH-3-furanyl                                     897 5-F,6-OMe CF.sub.3 CH═CH-2-thienyl                                     898 5-F,6-OMe CF.sub.3 CH═CH-3-thienyl                                     899 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                         900 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2                                      CH(CH.sub.3).sub.2                                 901 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                     902 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                903 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                  904 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                   905 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                            906 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                            907 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                            908 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                            909 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                            910 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                            911 5-F,6-OMe CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                            912 6-NMe.sub.2 CF.sub.3 C.tbd.C-nPr                                           913 6-NMe.sub.2 CF.sub.3 C.tbd.C-Bu                                            914 6-NMe.sub.2 CF.sub.3 C.tbd.C-iBu                                           915 6-NMe.sub.2 CF.sub.3 C.tbd.C-tBu                                           916 6-NMe.sub.2 CF.sub.3 C.tbd.C-Et                                            917 6-NMe.sub.2 CF.sub.3 C.tbd.C-Me                                            918 6-NMe.sub.2 CF.sub.3 C.tbd.C-Ph                                            919 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-Cl)Ph                                      920 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-Cl)Ph                                      921 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-F)Ph                                       922 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-F)Ph                                       923 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-OH)Ph                                      924 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-OH)Ph                                      925 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-OMe)Ph                                     926 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-OMe)Ph                                     927 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-CN)Ph                                      928 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-CN)Ph                                      929 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                930 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                931 6-NMe.sub.2 CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                               932 6-NMe.sub.2 CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                               933 6-NMe.sub.2 CF.sub.3 C.tbd.C-2-Pyridyl                                     934 6-NMe.sub.2 CF.sub.3 C.tbd.C-3-Pyridyl                                     935 6-NMe.sub.2 CF.sub.3 C.tbd.C-4-Pyridyl                                     936 6-NMe.sub.2 CF.sub.3 C.tbd.C-2-furanyl                                     937 6-NMe.sub.2 CF.sub.3 C.tbd.C-3-furanyl                                     938 6-NMe.sub.2 CF.sub.3 C.tbd.C-2-thienyl                                     939 6-NMe.sub.2 CF.sub.3 C.tbd.C-3-thienyl                                     940 6-NMe.sub.2 CF.sub.3 CH═CH-cycPr                                       941 6-NMe.sub.2 CF.sub.3 CH═CH-iPr                                         942 6-NMe.sub.2 CF.sub.3 CH═CH-nPr                                         943 6-NMe.sub.2 CF.sub.3 CH═CH-Bu                                          944 6-NMe.sub.2 CF.sub.3 CH═CH-iBu                                         945 6-NMe.sub.2 CF.sub.3 CH═CH-tBu                                         946 6-NMe.sub.2 CF.sub.3 CH═CH-Et                                          947 6-NMe.sub.2 CF.sub.3 CH═CH-Me                                          948 6-NMe.sub.2 CF.sub.3 CH═CH-Ph                                          949 6-NMe.sub.2 CF.sub.3 CH═CH-2-Pyridyl                                   950 6-NMe.sub.2 CF.sub.3 CH═CH-3-Pyridyl                                   951 6-NMe.sub.2 CF.sub.3 CH═CH-4-Pyridyl                                   952 6-NMe.sub.2 CF.sub.3 CH═CH-2-furanyl                                   953 6-NMe.sub.2 CF.sub.3 CH═CH-3-furanyl                                   954 6-NMe.sub.2 CF.sub.3 CH═CH-2-thienyl                                   955 6-NMe.sub.2 CF.sub.3 CH═CH-3-thienyl                                   956 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                   957 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                              958 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                959 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                 960 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                          961 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                          962 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                          963 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                          964 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                          965 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                          966 6-NMe.sub.2 CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                          967 6-COCH.sub.3 CF.sub.3 C.tbd.C-iPr                                          968 6-COCH.sub.3 CF.sub.3 C.tbd.C-nPr                                          969 6-COCH.sub.3 CF.sub.3 C.tbd.C-Bu                                           970 6-COCH.sub.3 CF.sub.3 C.tbd.C-iBu                                          971 6-COCH.sub.3 CF.sub.3 C.tbd.C-tBu                                          972 6-COCH.sub.3 CF.sub.3 C.tbd.C-Me                                           973 6-COCH.sub.3 CF.sub.3 C.tbd.C-Ph                                           974 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-Cl)Ph                                     975 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-Cl)Ph                                     976 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-F)Ph                                      977 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-F)Ph                                      978 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-OH)Ph                                     979 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-CH)Ph                                     980 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-OMe)Ph                                    981 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-OMe)Ph                                    982 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-CN)Ph                                     983 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-CN)Ph                                     984 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                               985 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                               986 6-COCH.sub.3 CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                              987 6-COCH.sub.3 CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                              988 6-COCH.sub.3 CF.sub.3 C.tbd.C-2-Pyridyl                                    989 6-COCH.sub.3 CF.sub.3 C.tbd.C-3-Pyridyl                                    990 6-COCH.sub.3 CF.sub.3 C.tbd.C-4-Pyridyl                                    991 6-COCH.sub.3 CF.sub.3 C.tbd.C-2-furanyl                                    992 6-COCH.sub.3 CF.sub.3 C.tbd.C-3-furanyl                                    993 6-COCH.sub.3 CF.sub.3 C.tbd.C-2-thienyl                                    994 6-COCH.sub.3 CF.sub.3 C.tbd.C-3-thienyl                                    995 6-COCH.sub.3 CF.sub.3 CH═CH-cycPr                                      996 6-COCH.sub.3 CF.sub.3 CH═CH-iPr                                        997 6-COCH.sub.3 CF.sub.3 CH═CH-nPr                                        998 6-COCH.sub.3 CF.sub.3 CH═CH-Bu                                         999 6-COCH.sub.3 CF.sub.3 CH═CH-iBu                                        1000 6-COCH.sub.3 CF.sub.3 CH═CH-tBu                                       1001 6-COCH.sub.3 CF.sub.3 CH═CH-Et                                        1002 6-COCH.sub.3 CF.sub.3 CH═CH-Me                                        1003 6-COCH.sub.3 CF.sub.3 CH═CH-Ph                                        1004 6-COCH.sub.3 CF.sub.3 CH═CH-2-Pyridyl                                 1005 6-COCH.sub.3 CF.sub.3 CH═CH-3-Pyridyl                                 1006 6-COCH.sub.3 CF.sub.3 CH═CH-4-Pyridyl                                 1007 6-COCH.sub.3 CF.sub.3 CH═CH-2-furanyl                                 1008 6-COCH.sub.3 CF.sub.3 CH═CH-3-furanyl                                 1009 6-COCH.sub.3 CF.sub.3 CH═CH-2-thienyl                                 1010 6-COCH.sub.3 CF.sub.3 CH═CH-3-thienyl                                 1011 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3        1012 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2                                             1013 6-COCH.sub.3 CF.sub.3 CH.sub.2                                           CH.sub.2 CH.sub.2 CH.sub.3                         1014 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                            1015 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -tBu                              1016 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -Ph                               1017 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                        1018 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                        1019 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                        1020 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                        1021 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                        1022 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                        1023 6-COCH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                        1024 6-CH.sub.3 CF.sub.3 C.tbd.C-nPr                                           1025 6-CH.sub.3 CF.sub.3 C.tbd.C-Bu                                            1026 6-CH.sub.3 CF.sub.3 C.tbd.C-iBu                                           1027 6-CH.sub.3 CF.sub.3 C.tbd.C-tBu                                           1028 6-CH.sub.3 CF.sub.3 C.tbd.C-Me                                            1029 6-CH.sub.3 CF.sub.3 C.tbd.C-Ph                                            1030 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-Cl)Ph                                      1031 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-Cl)Ph                                      1032 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-F)Ph                                       1033 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-F)Ph                                       1034 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-OH)Ph                                      1035 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-OH)Ph                                      1036 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-OMe)Ph                                     1037 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-OMe)Ph                                     1038 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-CN)Ph                                      1039 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-CN)Ph                                      1040 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-NH.sub.2)Ph                                1041 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-NH.sub.2)Ph                                1042 6-CH.sub.3 CF.sub.3 C.tbd.C-(2-NMe.sub.2)Ph                               1043 6-CH.sub.3 CF.sub.3 C.tbd.C-(3-NMe.sub.2)Ph                               1044 6-CH.sub.3 CF.sub.3 C.tbd.C-2-Pyridyl                                     1045 6-CH.sub.3 CF.sub.3 C.tbd.C-3-Pyridyl                                     1046 6-CH.sub.3 CF.sub.3 C.tbd.C-4-Pyridyl                                     1047 6-CH.sub.3 CF.sub.3 C.tbd.C-2-furanyl                                     1048 6-CH.sub.3 CF.sub.3 C.tbd.C-3-furanyl                                     1049 6-CH.sub.3 CF.sub.3 C.tbd.C-2-thienyl                                     1050 6-CH.sub.3 CF.sub.3 C.tbd.C-3-thienyl                                     1051 6-CH.sub.3 CF.sub.3 CH═CH-cycPr                                       1052 6-CH.sub.3 CF.sub.3 CH═CH-iPr                                         1053 6-CH.sub.3 CF.sub.3 CH═CH-nPr                                         1054 6-CH.sub.3 CF.sub.3 CH═CH-Bu                                          1055 6-CH.sub.3 CF.sub.3 CH═CH-iBu                                         1056 6-CH.sub.3 CF.sub.3 CH═CH-tBu                                         1057 6-CH.sub.3 CF.sub.3 CH═CH-Et                                          1058 6-CH.sub.3 CF.sub.3 CH═CH-Me                                          1059 6-CH.sub.3 CF.sub.3 CH═CH-Ph                                          1060 6-CH.sub.3 CF.sub.3 CH═CH-2-Pyridyl                                   1061 6-CH.sub.3 CF.sub.3 CH═CH-3-Pyridyl                                   1062 6-CH.sub.3 CF.sub.3 CH═CH-4-Pyridyl                                   1063 6-CH.sub.3 CF.sub.3 CH═CH-2-furanyl                                   1064 6-CH.sub.3 CF.sub.3 CH═CH-3-furanyl                                   1065 6-CH.sub.3 CF.sub.3 CH═CH-2-thienyl                                   1066 6-CH.sub.3 CF.sub.3 CH═CH-3-thienyl                                   1067 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                       1068 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2                                    CH(CH.sub.3).sub.2                                 1069 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                   1070 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                              1071 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -tBu                                1072 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                 1073 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                          1074 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                          1075 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                          1076 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                          1077 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                          1078 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                          1079 6-CH.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                          1080 6,8-diCl CF.sub.3 C.tbd.C-iPr                                             1081 6,8-diCl CF.sub.3 C.tbd.C-nPr                                             1082 6,8-diCl CF.sub.3 C.tbd.C-Et                                              1083 6,8-diCl CF.sub.3 C.tbd.C-Me                                              1084 6,8-diCl CF.sub.3 C.tbd.C-Ph                                              1085 6,8-diCl CF.sub.3 C.tbd.C-2-Pyridyl                                       1086 6,8-diCl CF.sub.3 C.tbd.C-3-Pyridyl                                       1087 6,8-diCl CF.sub.3 C.tbd.C-4-Pyridyl                                       1088 6,8-diCl CF.sub.3 C.tbd.C-2-furanyl                                       1089 6,8-diCl CF.sub.3 C.tbd.C-3-furanyl                                       1090 6,8-diCl CF.sub.3 C.tbd.C-2-thienyl                                       1091 6,8-diCl CF.sub.3 C.tbd.C-3-thienyl                                       1092 6,8-diCl CF.sub.3 CH═CH-cycPr                                         1093 6,8-diCl CF.sub.3 CH═CH-iPr                                           1094 6,8-diCl CF.sub.3 CH═CH-nPr                                           1095 6,8-diCl CF.sub.3 CH═CH-Et                                            1096 6,8-diCl CF.sub.3 CH═CH-Me                                            1097 6,8-diCl CF.sub.3 CH═CH-Ph                                            1098 6,8-diCl CF.sub.3 CH═CH-2-Pyridyl                                     1099 6,8-diCl CF.sub.3 CH═CH-3-Pyridyl                                     1100 6,8-diCl CF.sub.3 CH═CH-4-Pyridyl                                     1101 6,8-diCl CF.sub.3 CH═CH-2-furanyl                                     1102 6,8-diCl CF.sub.3 CH═CH-3-furanyl                                     1103 6,8-diCl CF.sub.3 CH═CH-2-thienyl                                     1104 6,8-diCl CF.sub.3 CH═CH-3-thienyl                                     1105 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                         1106 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2                                      CH(CH.sub.3).sub.2                                 1107 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                     1108 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                1109 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                            1110 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                            1111 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                            1112 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                            1113 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                            1114 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                            1115 6,8-diCl CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                            1116 5,6,8-triF CF.sub.3 C.tbd.C-Me                                            1117 5,6,8-triF CF.sub.3 C.tbd.C-Ph                                            1118 5,6,8-triF CF.sub.3 C.tbd.C-2-Pyridyl                                     1119 5,6,8-triF CF.sub.3 C.tbd.C-3-Pyridyl                                     1120 5,6,8-triF CF.sub.3 C.tbd.C-4-Pyridyl                                     1121 5,6,8-triF CF.sub.3 C.tbd.C-2-furanyl                                     1122 5,6,8-triF CF.sub.3 C.tbd.C-3-furanyl                                     1123 5,6,8-triF CF.sub.3 C.tbd.C-2-thienyl                                     1124 5,6,8-triF CF.sub.3 C.tbd.C-3-thienyl                                     1125 5,6,8-triF CF.sub.3 CH═CH-cycPr                                       1126 5,6,8-triF CF.sub.3 CH═CH-iPr                                         1127 5,6,8-triF CF.sub.3 CH═CH-nPr                                         1128 5,6,&-triF CF.sub.3 CH═CH-Et                                          1129 5,6,8-triF CF.sub.3 CH═CH-Me                                          1130 5,6,8-triF CF.sub.3 CH═CH-Ph                                          1131 5,6,8-triF CF.sub.3 CH═CH-2-Pyridyl                                   1132 5,6,8-triF CF.sub.3 CH═CH-3-Pyridyl                                   1133 5,6,8-triF CF.sub.3 CH═CH-4-Pyridyl                                   1134 5,6,8-triF CF.sub.3 CH═CH-2-furanyl                                   1135 5,6,8-triF CF.sub.3 CH═CH-3-furanyl                                   1136 5,6,8-triF CF.sub.3 CH═CH-2-thienyl                                   1137 5,6,8-triF CF.sub.3 CH═CH-3-thienyl                                   1138 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                       1139 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2                                    CH(CH.sub.3).sub.2                                 1140 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                   1141 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                              1142 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                 1143 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                          1144 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                          1145 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                          1146 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                          1147 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                          1148 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                          1149 5,6,8-triF CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                          1150 5,8-diF CF.sub.3 C.tbd.C-Me                                               1151 5,8-diF CF.sub.3 C.tbd.C-Ph                                               1152 5,8-diF CF.sub.3 C.tbd.C-2-Pyridyl                                        1153 5,8-diF CF.sub.3 C.tbd.C-3-Pyridyl                                        1154 5,8-diF CF.sub.3 C.tbd.C-4-Pyridyl                                        1155 5,8-diF CF.sub.3 C.tbd.C-2-furanyl                                        1156 5,8-diF CF.sub.3 C.tbd.C-3-furanyl                                        1157 5,8-diF CF.sub.3 C.tbd.C-2-thienyl                                        1158 5,8-diF CF.sub.3 C.tbd.C-3-thienyl                                        1159 5,8-diF CF.sub.3 CH═CH-cycPr                                          1160 5,8-diF CF.sub.3 CH═CH-iPr                                            1161 5,8-diF CF.sub.3 CH═CH-nPr                                            1162 5,8-diF CF.sub.3 CH═CH-Et                                             1163 5,8-diF CF.sub.3 CH═CH-Me                                             1164 5,8-diF CF.sub.3 CH═CH-Ph                                             1165 5,8-diF CF.sub.3 CH═CH-2-Pyridyl                                      1166 5,8-diF CF.sub.3 CH═CH-3-Pyridyl                                      1167 5,8-diF CF.sub.3 CH═CH-4-Pyridyl                                      1168 5,8-diF CF.sub.3 CH═CH-2-furanyl                                      1169 5,8-diF CF.sub.3 CH═CH-3-furanyl                                      1170 5,8-diF CF.sub.3 CH═CH-2-thienyl                                      1171 5,8-diF CF.sub.3 CH═CH-3-thienyl                                      1172 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                          1173 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2                                       CH(CH.sub.3).sub.2                                 1174 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                      1175 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                 1176 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                    1177 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                             1178 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                             1179 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                             1180 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                             1181 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                             1182 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                             1183 5,8-diF CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                             1184 6-iPr CF.sub.3 C.tbd.C-nPr                                                1185 6-iPr CF.sub.3 C.tbd.C-Et                                                 1186 6-iPr CF.sub.3 C.tbd.C-Me                                                 1187 6-iPr CF.sub.3 C.tbd.C-3-Pyridyl                                          1188 6-iPr CF.sub.3 C.tbd.C-2-furanyl                                          1189 6-iPr CF.sub.3 C.tbd.C-3-furanyl                                          1190 6-iPr CF.sub.3 C.tbd.C-2-thienyl                                          1191 6-iPr CF.sub.3 C.tbd.C-3-thienyl                                          1192 6-iPr CF.sub.3 CH═CH-cycPr                                            1193 6-iPr CF.sub.3 CH═CH-iPr                                              1194 6-iPr CF.sub.3 CH═CH-nPr                                              1195 6-iPr CF.sub.3 CH═CH-Et                                               1196 6-iPr CF.sub.3 CH═CH-Me                                               1197 6-iPr CF.sub.3 CH═CH-Ph                                               1198 6-iPr CF.sub.3 CH═CH-2-furanyl                                        1199 6-iPr CF.sub.3 CH═CH-3-furanyl                                        1200 6-iPr CF.sub.3 CH═CH-2-thienyl                                        1201 6-iPr CF.sub.3 CH═CH-3-thienyl                                        1202 6-iPr CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                        1203 6-iPr CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                   1204 6-OCF.sub.3 CF.sub.3 C.tbd.C-nPr                                          1205 6-OCF.sub.3 CF.sub.3 C.tbd.C-Et                                           1206 6-OCF.sub.3 CF.sub.3 C.tbd.C-Me                                           1207 6-OCF.sub.3 CF.sub.3 C.tbd.C-3-Pyridyl                                    1208 6-OCF.sub.3 CF.sub.3 C.tbd.C-2-furanyl                                    1209 6-OCF.sub.3 CF.sub.3 C.tbd.C-3-furanyl                                    1210 6-OCF.sub.3 CF.sub.3 C.tbd.C-2-thienyl                                    1211 6-OCF.sub.3 CF.sub.3 C.tbd.C-3-thienyl                                    1212 6-OCF.sub.3 CF.sub.3 CH═CH-cycPr                                      1213 6-OCF.sub.3 CF.sub.3 CH═CH-iPr                                        1214 6-OCF.sub.3 CF.sub.3 CH═CH-nPr                                        1215 6-OCF.sub.3 CF.sub.3 CH═CH-Et                                         1216 6-OCF.sub.3 CF.sub.3 CH═CH-Me                                         1217 6-OCF.sub.3 CF.sub.3 CH═CH-Ph                                         1218 6-OCF.sub.3 CF.sub.3 CH═CH-3-Pyridyl                                  1219 6-OCF.sub.3 CF.sub.3 CH═CH-2-furanyl                                  1220 6-OCF.sub.3 CF.sub.3 CH═CH-3-furanyl                                  1221 6-OCF.sub.3 CF.sub.3 CH═CH-2-thienyl                                  1222 6-OCF.sub.3 CF.sub.3 CH═CH-3-thienyl                                  1223 6-OCF.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  1224 6-OCF.sub.3 CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             1225 6-(pyrazol- CF.sub.3 C.tbd.C-cycPr                                         5-yl)                                                                         1226 6-(pyrazol- CF.sub.3 C.tbd.C-iPr                                           5-yl)                                                                         1227 6-(pyrazol- CF.sub.3 C.tbd.C-nPr                                           5-yl)                                                                         1228 6-(pyrazol- CF.sub.3 C.tbd.C-Et                                            5-yl)                                                                         1229 6-(pyrazol- CF.sub.3 C.tbd.C-Me                                            5-yl)                                                                         1230 6-(pyrazol- CF.sub.3 C.tbd.C-Ph                                            5-yl)                                                                         1231 6-(pyrazol- CF.sub.3 C.tbd.C-3-Pyridyl                                     5-yl)                                                                         1232 6-(pyrazol- CF.sub.3 C.tbd.C-2-furanyl                                     5-yl)                                                                         1233 6-(pyrazol- CF.sub.3 C.tbd.C-3-furanyl                                     5-yl)                                                                         1234 6-(pyrazol- CF.sub.3 C.tbd.C-2-thienyl                                     5-yl)                                                                         1235 6-(pyrazol- CF.sub.3 C.tbd.C-3-thienyl                                     5-yl)                                                                         1236 6-(pyrazol- CF.sub.3 CH═CH-cycPr                                       5-yl)                                                                         1237 6-(pyrazol- CF.sub.3 CH═CH-iPr                                         5-yl)                                                                         1238 6-(pyrazol- CF.sub.3 CH═CH-nPr                                         5-yl)                                                                         1239 6-(pyrazol- CF.sub.3 CH═CH-Et                                          5-yl)                                                                         1240 6-(pyrazol- CF.sub.3 CH═CH-Me                                          5-yl)                                                                         1241 6-(pyrazol- CF.sub.3 CH═CH-Ph                                          5-yl)                                                                         1242 6-(pyrazol- CF.sub.3 CH═CH-3-Pyridyl                                   5-yl)                                                                         1243 6-(pyrazol- CF.sub.3 CH═CH-2-furanyl                                   5-yl)                                                                         1244 6-(pyrazol- CF.sub.3 CH═CH-3-furanyl                                   5-yl)                                                                         1245 6-(pyrazol- CF.sub.3 CH═CH-2-thienyl                                   5-yl)                                                                         1246 6-(pyrazol- CF.sub.3 CH═CH-3-thienyl                                   5-yl)                                                                         1247 6-(pyrazol- CF.sub.3 Pentyl                                                5-yl)                                                                         1248 6-(pyrazol- CF.sub.3 CH.sub.2 CH.sub.2 -iPr                                5-yl)                                                                         1249 6-(pyrazol- CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                   5-yl)                                                                         1250 6-(pyrazol- CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                              5-yl)                                                                         1251 H CF.sub.3 C.tbd.C-nPr                                                    1252 H CF.sub.3 C.tbd.C-Et                                                     1253 H CF.sub.3 C.tbd.C-Me                                                     1254 H CF.sub.3 C.tbd.C-3-Pyridyl                                              1255 H CF.sub.3 C.tbd.C-2-furanyl                                              1256 H CF.sub.3 C.tbd.C-3-furanyl                                              1257 H CF.sub.3 C.tbd.C-2-thienyl                                              1258 H CF.sub.3 C.tbd.C-3-thienyl                                              1259 H CF.sub.3 CH═CH-cycPr                                                1260 H CF.sub.3 CH═CH-iPr                                                  1261 H CF.sub.3 CH═CH-nPr                                                  1262 H CF.sub.3 CH═CH-Et                                                   1263 H CF.sub.3 CH═CH-Me                                                   1264 H CF.sub.3 CH═CH-Ph                                                   1265 H CF.sub.3 CH═CH-3-Pyridyl                                            1266 H CF.sub.3 CH═CH-2-furanyl                                            1267 H CF.sub.3 CH═CH-3-furanyl                                            1268 H CF.sub.3 CH═CH-2-thienyl                                            1269 H CF.sub.3 CH═CH-3-thienyl                                            1270 H CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                            1271 H CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                       1272 6-Ph CF.sub.3 C.tbd.C-Me                                                  1273 6-Ph CF.sub.3 C.tbd.C-Ph                                                  1274 6-Ph CF.sub.3 C.tbd.C-3-Pyridyl                                           1275 6-Ph CF.sub.3 C.tbd.C-2-furanyl                                           1276 6-Ph CF.sub.3 C.tbd.C-3-furanyl                                           1277 6-Ph CF.sub.3 C.tbd.C-2-thienyl                                           1278 6-Ph CF.sub.3 C.tbd.C-3-thienyl                                           1279 6-Ph CF.sub.3 CH═CH-cycPr                                             1280 6-Ph CF.sub.3 CH═CH-iPr                                               1281 6-Ph CF.sub.3 CH═CH-nPr                                               1282 6-Ph CF.sub.3 CH═CH-Et                                                1283 6-Ph CF.sub.3 CH═CH-Me                                                1284 6-Ph CF.sub.3 CH═CH-Ph                                                1285 6-Ph CF.sub.3 CH═CH-3-Pyridyl                                         1286 6-Ph CF.sub.3 CH═CH-2-furanyl                                         1287 6-Ph CF.sub.3 CH═CH-3-furanyl                                         1288 6-Ph CF.sub.3 CH═CH-2-thienyl                                         1289 6-Ph CF.sub.3 CH═CH-3-thienyl                                         1290 6-Ph CF.sub.3 Pentyl                                                      1291 6-Ph CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                         1292 6-Ph CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                                    1293 6-CN CF.sub.3 C.tbd.C-cycPr                                               1294 6-CN CF.sub.3 C.tbd.C-iPr                                                 1295 6-CN CF.sub.3 C.tbd.C-nPr                                                 1296 6-CN CF.sub.3 C.tbd.C-Et                                                  1297 6-CN CF.sub.3 C.tbd.C-3-Pyridyl                                           1298 6-CN CF.sub.3 C.tbd.C-2-furanyl                                           1299 6-CN CF.sub.3 C.tbd.C-3-furanyl                                           1300 6-CN CF.sub.3 C.tbd.C-2-thienyl                                           1301 6-CN CF.sub.3 C.tbd.C-3-thienyl                                           1302 6-CN CF.sub.3 CH═CH-cycPr                                             1303 6-CN CF.sub.3 CH═CH-iPr                                               1304 6-CN CF.sub.3 CH═CH-nPr                                               1305 6-CN CF.sub.3 CH═CH-Et                                                1306 6-CN CF.sub.3 CH═CH-3-Pyridyl                                         1307 6-CN CF.sub.3 CH═CH-2-furanyl                                         1308 6-CN CF.sub.3 CH═CH-3-furanyl                                         1309 6-CN CF.sub.3 CH═CH-2-thienyl                                         1310 6-CN CF.sub.3 CH═CH-3-thienyl                                         1311 6-NO.sub.2 CF.sub.3 C.tbd.C-cycPr                                         1312 6-NO.sub.2 CF.sub.3 C.tbd.C-iPr                                           1313 6-NO.sub.2 CF.sub.3 C.tbd.C-nPr                                           1314 6-NO.sub.2 CF.sub.3 C.tbd.C-Et                                            1315 6-NO.sub.2 CF.sub.3 C.tbd.C-3-Pyridyl                                     1316 6-NO.sub.2 CF.sub.3 C.tbd.C-2-furanyl                                     1317 6-NO.sub.2 CF.sub.3 C.tbd.C-3-furanyl                                     1318 6-NO.sub.2 CF.sub.3 C.tbd.C-2-thienyl                                     1319 6-NO.sub.2 CF.sub.3 C.tbd.C-3-thienyl                                     1320 6-NHMe CF.sub.3 C.tbd.C-cycPr                                             1321 6-NHMe CF.sub.3 C.tbd.C-iPr                                               1322 6-NHMe CF.sub.3 C.tbd.C-nPr                                               1323 6-NHMe CF.sub.3 C.tbd.C-Et                                                1324 6-NHMe CF.sub.3 C.tbd.C-3-Pyridyl                                         1325 6-NHMe CF.sub.3 C.tbd.C-2-furanyl                                         1326 6-NHMe CF.sub.3 C.tbd.C-3-furanyl                                         1327 6-NHMe CF.sub.3 C.tbd.C-2-thienyl                                         1328 6-NHMe CF.sub.3 C.tbd.C-3-thienyl                                         1329 6-NHMe CF.sub.3 CH═CH-cycPr                                           1330 6-NHMe CF.sub.3 CH═CH-iPr                                             1331 6-NHMe CF.sub.3 CH═CH-nPr                                             1332 6-NHMe CF.sub.3 CH═CH-Et                                              1333 6-NHMe CF.sub.3 CH═CH-3-Pyridyl                                       1334 6-NHMe CF.sub.3 CH═CH-2-furanyl                                       1335 6-NHMe CF.sub.3 CH═CH-3-furanyl                                       1336 6-NHMe CF.sub.3 CH═CH-2-thienyl                                       1337 6-NHMe CF.sub.3 CH═CH-3-thienyl                                       1338 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-cycPr                                  1339 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-iPr                                    1340 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-nPr                                    1341 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-Et                                     1342 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-Pyridyl                              1343 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-furanyl                              1344 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-furanyl                              1345 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-2-thienyl                              1346 6,7-OCH.sub.2 O-- CF.sub.3 C.tbd.C-3-thienyl                              1347 6,7-diCl CF.sub.3 C.tbd.C-cycPr                                           1348 6,7-diCl CF.sub.3 C.tbd.C-iPr                                             1349 6,7-diCl CF.sub.3 C.tbd.C-nPr                                             1350 6,7-diCl CF.sub.3 C.tbd.C-Et                                              1351 6,7-diCl CF.sub.3 C.tbd.C-3-Pyridyl                                       1352 6,7-diCl CF.sub.3 C.tbd.C-2-furanyl                                       1353 6,7-diCl CF.sub.3 C.tbd.C-3-furanyl                                       1354 6,7-diCl CF.sub.3 C.tbd.C-2-thienyl                                       1355 6,7-diCl CF.sub.3 C.tbd.C-3-thienyl                                       1356 7-Cl CF.sub.3 C.tbd.C-cycPr                                               1357 7-Cl CF.sub.3 C.tbd.C-iPr                                                 1358 7-Cl CF.sub.3 C.tbd.C-nPr                                                 1359 7-Cl CF.sub.3 C.tbd.C-Et                                                  1360 7-Cl CF.sub.3 C.tbd.C-3-Pyridyl                                           1361 7-Cl CF.sub.3 C.tbd.C-2-furanyl                                           1362 7-Cl CF.sub.3 C.tbd.C-3-furanyl                                           1363 7-Cl CF.sub.3 C.tbd.C-2-thienyl                                           1364 7-Cl CF.sub.3 C.tbd.C-3-thienyl                                         ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-)                        

                  TABLE 3                                                          ______________________________________                                           #STR44##                                                                       Ex. #      G            R.sup.1                                                                               R.sup.2                                       ______________________________________                                         1401     6-Cl,8-F     cycPr    C.tbd.C-cycPr                                     1402 6-Cl,8-F cycPr C.tbd.C-iPr                                                1403 6-Cl,8-F cycPr C.tbd.C-nPr                                                1404 6-Cl,8-F cycPr C.tbd.C-Et                                                 1405 6-Cl,8-F cycPr C.tbd.C-3-Pyridyl                                          1406 6-Cl,8-F cycPr C.tbd.C-2-furanyl                                          1407 6-Cl,8-F cycPr C.tbd.C-3-furanyl                                          1408 6-Cl,8-F cycPr C.tbd.C-2-thienyl                                          1409 6-Cl,8-F cycPr C.tbd.C-3-thienyl                                          1410 6-Cl,8-F iPr C.tbd.C-cycPr                                                1411 6-Cl,8-F iPr C.tbd.C-iPr                                                  1412 6-Cl,8-F iPr C.tbd.C-nPr                                                  1413 6-Cl,8-F iPr C.tbd.C-Et                                                   1414 6-Cl,8-F iPr C.tbd.C-3-Pyridyl                                            1415 6-Cl,8-F iPr C.tbd.C-2-furanyl                                            1416 6-Cl,8-F iPr C.tbd.C-3-furanyl                                            1417 6-Cl,8-F iPr C.tbd.C-2-thienyl                                            1418 6-Cl,8-F iPr C.tbd.C-3-thienyl                                            1419 6-Cl,8-F Et C.tbd.C-cycPr                                                 1420 6-Cl,8-F Et C.tbd.C-iPr                                                   1421 6-Cl,8-F Et C.tbd.C-nPr                                                   1422 6-Cl,8-F Et C.tbd.C-Et                                                    1423 5,6-diF cycPr C.tbd.C-cycPr                                               1424 5,6-diF cycPr C.tbd.C-iPr                                                 1425 5,6-diF cycPr C.tbd.C-nPr                                                 1426 5,6-diF cycPr C.tbd.C-Et                                                  1427 5,6-diF cycPr C.tbd.C-3-Pyridyl                                           1428 5,6-diF cycPr C.tbd.C-2-furanyl                                           1429 5,6-diF cycPr C.tbd.C-3-furanyl                                           1430 5,6-diF cycPr C.tbd.C-2-thienyl                                           1431 5,6-diF cycPr C.tbd.C-3-thienyl                                           1432 5,6-diF iPr C.tbd.C-cycPr                                                 1433 5,6-diF iPr C.tbd.C-iPr                                                   1434 5,6-diF iPr C.tbd.C-nPr                                                   1435 5,6-diF iPr C.tbd.C-Et                                                    1436 5,6-diF iPr C.tbd.C-3-Pyridyl                                             1437 5,6-diF iPr C.tbd.C-2-furanyl                                             1438 5,6-diF iPr C.tbd.C-3-furanyl                                             1439 5,6-diF iPr C.tbd.C-2-thienyl                                             1440 5,6-diF iPr C.tbd.C-3-thienyl                                             1441 5,6-diF Et C.tbd.C-cycPr                                                  1442 5,6-diF Et C.tbd.C-iPr                                                    1443 5,6-diF Et C.tbd.C-nPr                                                    1444 5,6-diF Et C.tbd.C-Et                                                     1445 5,6-diCl cycPr C.tbd.C-cycPr                                              1446 5,6-diCl cycPr C.tbd.C-iPr                                                1447 5,6-diCl cycPr C.tbd.C-nPr                                                1448 5,6-diCl cycPr C.tbd.C-Et                                                 1449 5,6-diCl cycPr C.tbd.C-3-Pyridyl                                          1450 5,6-diCl cycPr C.tbd.C-2-furanyl                                          1451 5,6-diCl cycPr C.tbd.C-3-furanyl                                          1452 5,6-diCl cycPr C.tbd.C-2-thienyl                                          1453 5,6-diCl cycPr C.tbd.C-3-thienyl                                          1454 5,6-diCl iPr C.tbd.C-cycPr                                                1455 5,6-diCl iPr C.tbd.C-iPr                                                  1456 5,6-diCl iPr C.tbd.C-nPr                                                  1457 5,6-diCl iPr C.tbd.C-Et                                                   1458 5,6-diCl iPr C.tbd.C-3-Pyridyl                                            1459 5,6-diCl iPr C.tbd.C-2-furanyl                                            1460 5,6-diCl iPr C.tbd.C-3-furanyl                                            1461 5,6-diCl iPr C.tbd.C-2-thienyl                                            1462 5,6-diCl iPr C.tbd.C-3-thienyl                                            1463 5,6-diCl Et C.tbd.C-cycPr                                                 1464 5,6-diCl Et C.tbd.C-iPr                                                   1465 5,6-diCl Et C.tbd.C-nPr                                                   1466 5,6-diCl Et C.tbd.C-Et                                                    1467 5-Cl,6-F cycPr C.tbd.C-cycPr                                              1468 5-Cl,6-F cycPr C.tbd.C-iPr                                                1469 5-Cl,6-F cycPr C.tbd.C-nPr                                                1470 5-Cl,6-F cycPr C.tbd.C-Et                                                 1471 5-Cl,6-F cycPr C.tbd.C-3-Pyridyl                                          1472 5-Cl,6-F cycPr C.tbd.C-2-furanyl                                          1473 5-Cl,6-F cycPr C.tbd.C-3-furanyl                                          1474 5-Cl,6-F cycPr C.tbd.C-2-thienyl                                          1475 5-Cl,6-F cycPr C.tbd.C-3-thienyl                                          1476 5-Cl,6-F iPr C.tbd.C-cycPr                                                1477 5-Cl,6-F iPr C.tbd.C-iPr                                                  1478 5-Cl,6-F iPr C.tbd.C-nPr                                                  1479 5-Cl,6-F iPr C.tbd.C-Et                                                   1480 5-Cl,6-F iPr C.tbd.C-3-Pyridyl                                            1481 5-Cl,6-F iPr C.tbd.C.tbd.C-2-furanyl                                      1482 5-Cl,6-F iPr C.tbd.C-3-furanyl                                            1483 5-Cl,6-F iPr C.tbd.C-2-thienyl                                            1484 5-Cl,6-F iPr C.tbd.C-3-thienyl                                            1485 5-Cl,6-F Et C.tbd.C-cycPr                                                 1486 5-Cl,6-F Et C.tbd.C-iPr                                                   1487 5-Cl,6-F Et C.tbd.C-nPr                                                   1488 5-Cl,6-F Et C.tbd.C-Et                                                    1489 5,6-OCH.sub.2 O-- cycPr C.tbd.C-cycPr                                     1490 5,6-OCH.sub.2 O-- cycPr C.tbd.C-iPr                                       1491 5,6-OCH.sub.2 O-- cycPr C.tbd.C-nPr                                       1492 5,6-OCH.sub.2 O-- cycPr C.tbd.C-Et                                        1493 5,6-OCH.sub.2 O-- cycPr C.tbd.C-3-Pyridyl                                 1494 5,6-OCH.sub.2 O-- cycPr C.tbd.C-2-furanyl                                 1495 5,6-OCH.sub.2 O-- cycPr C.tbd.C-3-furanyl                                 1496 5,6-OCH.sub.2 O-- cycPr C.tbd.C-2-thienyl                                 1497 5,6-OCH.sub.2 O-- cycPr C.tbd.C-3-thienyl                                 1498 5,6-OCH.sub.2 O-- iPr C.tbd.C-cycPr                                       1499 5,6-OCH.sub.2 O-- iPr C.tbd.C-iPr                                         1500 5,6-OCH.sub.2 O-- iPr C.tbd.C-nPr                                         1501 5,6-OCH.sub.2 O-- iPr C.tbd.C-Et                                          1502 5,6-OCH.sub.2 O-- iPr C.tbd.C-3-Pyridyl                                   1503 5,6-OCH.sub.2 O-- iPr C.tbd.C-2-furanyl                                   1504 5,6-OCH.sub.2 O-- iPr C.tbd.C-3-furanyl                                   1505 5,6-OCH.sub.2 O-- iPr C.tbd.C-2-thienyl                                   1506 5,6-OCH.sub.2 O-- iPr C.tbd.C-3-thienyl                                   1507 5,6-OCH.sub.2 O-- Et C.tbd.C-cycPr                                        1508 5,6-OCH.sub.2 O-- Et C.tbd.C-iPr                                          1509 5,6-OCH.sub.2 O-- Et C.tbd.C-nPr                                          1510 5,6-OCH.sub.2 O-- Et C.tbd.C-Et                                           1511 5-F cycPr C.tbd.C-cycPr                                                   1512 5-F cycPr C.tbd.C-iPr                                                     1513 5-F cycPr C.tbd.C-nPr                                                     1514 5-F cycPr C.tbd.C-Et                                                      1515 5-F cycPr C.tbd.C-3-Pyridyl                                               1516 5-F cycPr C.tbd.C-2-furanyl                                               1517 5-F cycPr C.tbd.C-3-furanyl                                               1518 5-F cycPr C.tbd.C-2-thienyl                                               1519 5-F cycPr C.tbd.C-3-thienyl                                               1520 5-F iPr C.tbd.C-cycPr                                                     1521 5-F iPr C.tbd.C-iPr                                                       1522 5-F iPr C.tbd.C-nPr                                                       1523 5-F iPr C.tbd.C-Et                                                        1524 5-F iPr C.tbd.C-3-Pyridyl                                                 1525 5-F iPr C.tbd.C-2-furanyl                                                 1526 5-F iPr C.tbd.C-3-furanyl                                                 1527 5-F iPr C.tbd.C-2-thienyl                                                 1528 5-F iPr C.tbd.C-3-thienyl                                                 1529 5-F Et C.tbd.C-cycPr                                                      1530 5-F Et C.tbd.C-iPr                                                        1531 5-F Et C.tbd.C-nPr                                                        1532 5-F Et C.tbd.C-Et                                                         1533 5-Cl cycPr C.tbd.C-cycPr                                                  1534 5-Cl cycPr C.tbd.C-iPr                                                    1535 5-Cl cycPr C.tbd.C-nPr                                                    1536 5-Cl cycPr C.tbd.C-Et                                                     1537 5-Cl cycPr C.tbd.C-3-Pyridyl                                              1538 5-Cl cycPr C.tbd.C-2-furanyl                                              1539 5-Cl cycPr C.tbd.C-3-furanyl                                              1540 5-Cl cycPr C.tbd.C-2-thienyl                                              1541 5-Cl cycPr C.tbd.C-3-thienyl                                              1542 5-Cl iPr C.tbd.C-cycPr                                                    1543 5-Cl iPr C.tbd.C-iPr                                                      1544 5-Cl iPr C.tbd.C-nPr                                                      1545 5-Cl iPr C.tbd.C-Et                                                       1546 5-Cl iPr C.tbd.C-3-Pyridyl                                                1547 5-Cl iPr C.tbd.C-2-furanyl                                                1548 5-Cl iPr C.tbd.C-3-furanyl                                                1549 5-Cl iPr C.tbd.C-2-thienyl                                                1550 5-Cl iPr C.tbd.C-3-thienyl                                                1551 5-Cl Et C.tbd.C-cycPr                                                     1552 5-Cl Et C.tbd.C-iPr                                                       1553 5-Cl Et C.tbd.C-nPr                                                       1554 5-Cl Et C.tbd.C-Et                                                        1555 6-OMe cycPr C.tbd.C-cycPr                                                 1556 6-OMe cycPr C.tbd.C-iPr                                                   1557 6-OMe cycPr C.tbd.C-nPr                                                   1558 6-OMe cycPr C.tbd.C-Et                                                    1559 6-OMe cycPr C.tbd.C-3-Pyridyl                                             1560 6-OMe cycPr C.tbd.C-2-furanyl                                             1561 6-OMe cycPr C.tbd.C-3-furanyl                                             1562 6-OMe cycPr C.tbd.C-2-thienyl                                             1563 6-OMe cycPr C.tbd.C-3-thienyl                                             1564 6-OMe iPr C.tbd.C-nPr                                                     1565 6-OMe iPr C.tbd.C-Et                                                      1566 6-OMe iPr C.tbd.C-3-Pyridyl                                               1567 6-OMe iPr C.tbd.C-2-furanyl                                               1568 6-OMe iPr C.tbd.C-3-furanyl                                               1569 6-OMe iPr C.tbd.C-2-thienyl                                               1570 6-OMe iPr C.tbd.C-3-thienyl                                               1571 6-OMe Et C.tbd.C-cycPr                                                    1572 6-OMe Et C.tbd.C-iPr                                                      1573 6-OMe Et C.tbd.C-nPr                                                      1574 6-OMe Et C.tbd.C-Et                                                       1575 5-F,6-OMe cycPr C.tbd.C-cycPr                                             1576 5-F,6-OMe cycPr C.tbd.C-iPr                                               1577 5-F,6-OMe cycPr C.tbd.C-nPr                                               1578 5-F,6-OMe cycPr C.tbd.C-Et                                                1579 5-F,6-OMe cycPr C.tbd.C-3-Pyridyl                                         1580 5-F,6-OMe cycPr C.tbd.C-2-furanyl                                         1581 5-F,6-OMe cycPr C.tbd.C-3-furanyl                                         1582 5-F,6-OMe cycPr C.tbd.C-2-thienyl                                         1583 5-F,6-OMe cycPr C.tbd.C-3-thienyl                                         1584 5-F,6-OMe iPr C.tbd.C-cycPr                                               1585 5-F,6-OMe iPr C.tbd.C-iPr                                                 1586 5-F,6-OMe iPr C.tbd.C-nPr                                                 1587 5-F,6-OMe iPr C.tbd.C-Et                                                  1588 5-F,6-OMe iPr C.tbd.C-3-Pyridyl                                           1589 5-F,6-OMe iPr C.tbd.C-2-furanyl                                           1590 5-F,6-OMe iPr C.tbd.C-3-furanyl                                           1591 5-F,6-OMe iPr C.tbd.C-2-thienyl                                           1592 5-F,6-OMe iPr C.tbd.C-3-thienyl                                           1593 5-F,6-OMe Et C.tbd.C-cycPr                                                1594 5-F,6-OMe Et C.tbd.C-iPr                                                  1595 5-F,6-OMe Et C.tbd.C-nPr                                                  1596 5-F,6-OMe Et C.tbd.C-Et                                                   1597 6-NMe.sub.2 cycPr C.tbd.C-cycPr                                           1598 6-NMe.sub.2 cycPr C.tbd.C-iPr                                             1599 6-NMe.sub.2 cycPr C.tbd.C-nPr                                             1600 6-NMe.sub.2 cycPr C.tbd.C-Et                                              1601 6-NMe.sub.2 cycPr C.tbd.C-3-Pyridyl                                       1602 6-NMe.sub.2 cycPr C.tbd.C-2-furanyl                                       1603 6-NMe.sub.2 cycPr C.tbd.C-3-furanyl                                       1604 6-NMe.sub.2 cycPr C.tbd.C-2-thienyl                                       1605 6-NMe.sub.2 cycPr C.tbd.C-3-thienyl                                       1606 6-NMe.sub.2 iPr C.tbd.C-cycPr                                             1607 6-NMe.sub.2 iPr C.tbd.C-iPr                                               1608 6-NMe.sub.2 iPr C.tbd.C-nPr                                               1609 6-NMe.sub.2 iPr C.tbd.C-Et                                                1610 6-NMe.sub.2 iPr C.tbd.C-3-Pyridyl                                         1611 6-NMe.sub.2 iPr C.tbd.C-2-furanyl                                         1612 6-NMe.sub.2 iPr C.tbd.C-3-furanyl                                         1613 6-NMe.sub.2 iPr C.tbd.C-2-thienyl                                         1614 6-NMe.sub.2 i-Pr C.tbd.C-3-thienyl                                        1615 6-NMe.sub.2 Et C.tbd.C-cycPr                                              1616 6-NMe.sub.2 Et C.tbd.C-iPr                                                1617 6-NMe.sub.2 Et C.tbd.C-nPr                                                1618 6-NMe.sub.2 Et C.tbd.C-Et                                                 1619 6-COCH.sub.3 cycPr C.tbd.C-cycPr                                          1620 6-COCH.sub.3 cycPr C.tbd.C-iPr                                            1621 6-COCH.sub.3 cycPr C.tbd.C-nPr                                            1622 6-COCH.sub.3 cycPr C.tbd.C-Et                                             1623 6-COCH.sub.3 cycPr C.tbd.C-3-Pyridyl                                      1624 6-COCH.sub.3 cycPr C.tbd.C-2-furanyl                                      1625 6-COCH.sub.3 cycPr C.tbd.C-3-furanyl                                      1626 6-COCH.sub.3 cycPr C.tbd.C-2-thienyl                                      1627 6-COCH.sub.3 cycPr C.tbd.C-3-thienyl                                      1628 6-COCH.sub.3 iPr C.tbd.C-cycPr                                            1629 6-COCH.sub.3 iPr C.tbd.C-iPr                                              1630 6-COCH.sub.3 iPr C.tbd.C-nPr                                              1631 6-COCH.sub.3 iPr C.tbd.C-Et                                               1632 6-COCH.sub.3 iPr C.tbd.C-3-Pyridyl                                        1633 6-COCH.sub.3 iPr C.tbd.C-2-furanyl                                        1634 6-COCH.sub.3 iPr C.tbd.C-3-furanyl                                        1635 6-COCH.sub.3 iPr C.tbd.C-2-thienyl                                        1636 6-COCH.sub.3 iPr C.tbd.C-3-thienyl                                        1637 6-COCH.sub.3 Et C.tbd.C-cycPr                                             1638 6-COCH.sub.3 Et C.tbd.C-iPr                                               1639 6-COCH.sub.3 Et C.tbd.C-nPr                                               1640 6-COCH.sub.3 Et C.tbd.C-Et                                                1641 6-CH.sub.3 cycPr C.tbd.C-cycPr                                            1642 6-CH.sub.3 cycPr C.tbd.C-nPr                                              1643 6-CH.sub.3 cycPr C.tbd.C-Et                                               1644 6-CH.sub.3 cycPr C.tbd.C-3-Pyridyl                                        1645 6-CH.sub.3 cycPr C.tbd.C-2-furanyl                                        1646 6-CH.sub.3 cycPr C.tbd.C-3-furanyl                                        1647 6-CH.sub.3 cycPr C.tbd.C-2-thienyl                                        1648 6-CH.sub.3 cycPr C.tbd.C-3-thienyl                                        1649 6-CH.sub.3 iPr C.tbd.C-nPr                                                1650 6-CH.sub.3 iPr C.tbd.C-Et                                                 1651 6-CH.sub.3 iPr C.tbd.C-3-Pyridyl                                          1652 6-CH.sub.3 iPr C.tbd.C-2-furanyl                                          1653 6-CH.sub.3 iPr C.tbd.C-3-furanyl                                          1654 6-CH.sub.3 iPr C.tbd.C-2-thienyl                                          1655 6-CH.sub.3 iPr C.tbd.C-3-thienyl                                          1656 6-CH.sub.3 Et C.tbd.C-cycPr                                               1657 6-CH.sub.3 Et C.tbd.C-nPr                                                 1658 6,8-diCl cycPr C.tbd.C-cycPr                                              1659 6,8-diCl cycPr C.tbd.C-iPr                                                1660 6,8-diCl cycPr C.tbd.C-nPr                                                1661 6,8-diCl cycPr C.tbd.C-Et                                                 1662 6,8-diCl cycPr C.tbd.C-3-Pyridyl                                          1663 6,8-diCl cycPr C.tbd.C-2-furanyl                                          1664 6,8-diCl cycPr C.tbd.C-3-furanyl                                          1665 6,8-diCl cycPr C.tbd.C-2-thienyl                                          1666 6,8-diCl cycPr C.tbd.C-3-thienyl                                          1667 6,8-diCl iPr C.tbd.C-cycPr                                                1668 6,8-diCl iPr C.tbd.C-iPr                                                  1669 6,8-diCl iPr C.tbd.C-nPr                                                  1670 6,8-diCl iPr C.tbd.C-Et                                                   1671 6,8-diCl iPr C.tbd.C-3-Pyridyl                                            1672 6,8-diCl iPr C.tbd.C-2-furanyl                                            1673 6,8-diCl iPr C.tbd.C-3-furanyl                                            1674 6,8-diCl iPr C.tbd.C-2-thienyl                                            1675 6,8-diCl iPr C.tbd.C-3-thienyl                                            1676 6,8-diCl Et C.tbd.C-cycPr                                                 1677 6,8-diCl Et C.tbd.C-iPr                                                   1678 6,8-diCl Et C.tbd.C-nPr                                                   1679 6,8-diCl Et C.tbd.C-Et                                                    1680 5,6,8-triF cycPr C.tbd.C-cycPr                                            1681 5,6,8-triF cycPr C.tbd.C-iPr                                              1682 5,6,8-triF cycPr C.tbd.C-nPr                                              1683 5,6,8-triF cycPr C.tbd.C-Et                                               1684 5,6,8-triF cycPr C.tbd.C-3-Pyridyl                                        1685 5,6,8-triF cycPr C.tbd.C-2-furanyl                                        1686 5,6,8-triF cycPr C.tbd.C-3-furanyl                                        1687 5,6,8-triF cycPr C.tbd.C-2-thienyl                                        1688 5,6,8-triF cycPr C.tbd.C-3-thienyl                                        1689 5,6,8-triF iPr C.tbd.C-cycPr                                              1690 5,6,8-triF iPr C.tbd.C-iPr                                                1691 5,6,8-triF iPr C.tbd.C-nPr                                                1692 5,6,8-triF iPr C.tbd.C-Et                                                 1693 5,6,8-triF iPr C.tbd.C-3-Pyridyl                                          1694 5,6,8-triF iPr C.tbd.C-2-furanyl                                          1696 5,6,8-triF iPr C.tbd.C-2-thienyl                                          1697 5,6,8-triF iPr C.tbd.C-3-thienyl                                          1698 5,6,8-triF Et C.tbd.C-cycPr                                               1699 5,6,8-triF Et C.tbd.C-iPr                                                 1700 5,6,8-triF Et C.tbd.C-nPr                                                 1701 5,6,8-triF Et C.tbd.C-Et                                                  1702 5,8-diF cycPr C.tbd.C-cycPr                                               1703 5,8-diF cycPr C.tbd.C-iPr                                                 1704 518-diF cycPr C.tbd.C-nPr                                                 1705 5,8-diF cycPr C.tbd.C-Et                                                  1706 5,8-diF cycPr C.tbd.C-3-Pyridyl                                           1707 5,8-diF cycPr C.tbd.C-2-furanyl                                           1708 5,8-diF cycPr C.tbd.C-3-furanyl                                           1709 5,8-diF cycPr C.tbd.C-2-thienyl                                           1710 5,8-diF cycPr C.tbd.C-3-thienyl                                           1711 5,8-diF iPr C.tbd.C-cycPr                                                 1712 5,8-diF iPr C.tbd.C-iPr                                                   1713 5,8-diF iPr C.tbd.C-nPr                                                   1714 5,8-diF iPr C.tbd.C-Et                                                    1715 5,8-diF iPr C.tbd.C-3-Pyridyl                                             1716 5,8-diF iPr C.tbd.C-2-furanyl                                             1717 5,8-diF iPr C.tbd.C-3-furanyl                                             1718 5,8-diF iPr C.tbd.C-2-thienyl                                             1719 5,8-diF iPr C.tbd.C-3-thienyl                                             1720 5,8-diF Et C.tbd.C-cycPr                                                  1721 5,8-diF Et C.tbd.C-iPr                                                    1722 5,8-diF Et C.tbd.C-nPr                                                    1723 5,8-diF Et C.tbd.C-Et                                                     1724 6-iPr cycPr C.tbd.C-cycPr                                                 1725 6-iPr cycPr C.tbd.C-iPr                                                   1726 6-iPr cycPr C.tbd.C-nPr                                                   1727 6-iPr cycPr C.tbd.C-Et                                                    1728 6-iPr cycPr C.tbd.C-3-Pyridyl                                             1729 6-iPr cycPr C.tbd.C-2-furanyl                                             1730 6-iPr cycPr C.tbd.C-3-furanyl                                             1731 6-iPr cycPr C.tbd.C-2-thienyl                                             1732 6-iPr cycPr C.tbd.C-3-thienyl                                             1733 6-iPr iPr C.tbd.C-cycPr                                                   1734 6-iPr iPr C.tbd.C-iPr                                                     1735 6-iPr iPr C.tbd.C-nPr                                                     1736 6-iPr iPr C.tbd.C-Et                                                      1737 6-iPr iPr C.tbd.C-3-Pyridyl                                               1738 6-iPr iPr C.tbd.C-2-furanyl                                               1739 6-iPr iPr C.tbd.C-3-furanyl                                               1740 6-iPr iPr C.tbd.C-2-thienyl                                               1741 6-iPr iPr C.tbd.C-3-thienyl                                               1742 6-iPr Et C.tbd.C-cycPr                                                    1743 6-iPr Et C.tbd.C-iPr                                                      1744 6-iPr Et C.tbd.C-nPr                                                      1745 6-iPr Et C.tbd.C-Et                                                       1746 6-OCF.sub.3 cycPr C.tbd.C-cycPr                                           1747 6-OCF.sub.3 cycPr C.tbd.C-iPr                                             1748 6-OCF.sub.3 cycPr C.tbd.C-nPr                                             1749 6-OCF.sub.3 cycPr C.tbd.C-Et                                              1750 6-OCF.sub.3 cycPr C.tbd.C-3-Pyridyl                                       1751 6-OCF.sub.3 cycPr C.tbd.C-2-furanyl                                       1752 6-OCF.sub.3 cycPr C.tbd.C-3-furanyl                                       1753 6-OCF.sub.3 cycPr C.tbd.C-2-thienyl                                       1754 6-OCF.sub.3 cycPr C.tbd.C-3-thienyl                                       1755 6-OCF.sub.3 iPr C.tbd.C-cycPr                                             1756 6-OCF.sub.3 iPr C.tbd.C-iPr                                               1757 6-OCF.sub.3 iPr C.tbd.C-nPr                                               1758 6-OCF.sub.3 iPr C.tbd.C-Et                                                1759 6-OCF.sub.3 iPr C.tbd.C-3-Pyridyl                                         1760 6-OCF.sub.3 iPr C.tbd.C-2-furanyl                                         1761 6-OCF.sub.3 iPr C.tbd.C-3-furanyl                                         1762 6-OCF.sub.3 iPr C.tbd.C-2-thienyl                                         1763 6-OCF.sub.3 iPr C.tbd.C-3-thienyl                                         1764 6-OCF.sub.3 Et C.tbd.C-cycPr                                              1765 6-OCF.sub.3 Et C.tbd.C-iPr                                                1766 6-OCF.sub.3 Et C.tbd.C-nPr                                                1767 6-OCF.sub.3 Et C.tbd.C-Et                                                 1768 6-(pyrazol- cycPr C.tbd.C-cycPr                                            5-yl)                                                                         1769 6-(pyrazol- cycPr C.tbd.C-iPr                                              5-yl)                                                                         1770 6-(pyrazol- cycPr C.tbd.C-nPr                                              5-yl)                                                                         1771 6-(pyrazol- cycPr C.tbd.C-Et                                               5-yl)                                                                         1772 6-(pyrazol- cycPr C.tbd.C-3-Pyridyl                                        5-yl)                                                                         1773 6-(pyrazol- cycPr C.tbd.C-2-furanyl                                        5-yl)                                                                         1774 6-(pyrazol- cycPr C.tbd.C-3-furanyl                                        5-yl)                                                                         1775 6-(pyrazol- cycPr C.tbd.C-2-thienyl                                        5-yl)                                                                         1776 6-(pyrazol- cycPr C.tbd.C-3-thienyl                                        5-yl)                                                                         1777 6-(pyrazol- iPr C.tbd.C-cycPr                                              5-yl)                                                                         1778 6-(pyrazol- iPr C.tbd.C-iPr                                                5-yl)                                                                         1779 6-(pyrazol- iPr C.tbd.C-nPr                                                5-yl)                                                                         1780 6-(pyrazol- iPr C.tbd.C-Et                                                 5-yl)                                                                         1781 6-(pyrazol- iPr C.tbd.C-3-Pyridyl                                          5-yl)                                                                         1782 6-(pyrazol- iPr C.tbd.C-2-furanyl                                          5-yl)                                                                         1783 6-(pyrazol- iPr C.tbd.C-3-furanyl                                          5-yl)                                                                         1784 6-(pyrazol- iPr C.tbd.C-2-thienyl                                          5-yl)                                                                         1785 6-(pyrazol- iPr C.tbd.C-3-thienyl                                          5-yl)                                                                         1786 6-( pyrazol- Et C.tbd.C-cycPr                                              5-yl)                                                                         1787 6-(pyrazol- Et C.tbd.C-iPr                                                 5-yl)                                                                         1788 6-(pyrazol- Et C.tbd.C-nPr                                                 5-yl)                                                                         1789 6-(pyrazol- Et C.tbd.C-Et                                                  5-yl)                                                                         1790 H cycPr C.tbd.C-cycPr                                                     1791 H cycPr C.tbd.C-iPr                                                       1792 H cycPr C.tbd.C-nPr                                                       1793 H cycPr C.tbd.C-Et                                                        1794 H cycPr C.tbd.C-3-Pyridyl                                                 1795 H cycPr C.tbd.C-2-furanyl                                                 1796 H cycPr C.tbd.C-3-furanyl                                                 1797 H cycPr C.tbd.C-2-thienyl                                                 1798 H cycPr C.tbd.C-3-thienyl                                                 1799 H iPr C.tbd.C-cycPr                                                       1800 H iPr C.tbd.C-iPr                                                         1801 H iPr C.tbd.C-nPr                                                         1802 H iPr C.tbd.C-Et                                                          1803 H iPr C.tbd.C-3-Pyridyl                                                   1804 H iPr C.tbd.C-2-furanyl                                                   1805 H iPr C.tbd.C-3-furanyl                                                   1806 H iPr C.tbd.C-2-thienyl                                                   1807 H iPr C.tbd.C-3-thienyl                                                   1808 H Et C.tbd.C-cycPr                                                        1809 H Et C.tbd.C-iPr                                                          1810 H Et C.tbd.C-nPr                                                          1811 H Et C.tbd.C-Et                                                           1812 6-Ph cycPr C.tbd.C-cycPr                                                  1813 6-Ph cycPr C.tbd.C-iPr                                                    1814 6-Ph cycPr C.tbd.C-nPr                                                    1815 6-Ph cycPr C.tbd.C-Et                                                     1816 6-Ph cycPr C.tbd.C-3-Pyridyl                                              1817 6-Ph cycPr C.tbd.C-2-furanyl                                              1818 6-Ph cycPr C.tbd.C-3-furanyl                                              1819 6-Ph cycPr C.tbd.C-2-thienyl                                              1820 6-Ph cycPr C.tbd.C-3-thienyl                                              1821 6-Ph iPr C.tbd.C-cycPr                                                    1822 6-Ph iPr C.tbd.C-iPr                                                      1823 6-Ph iPr C.tbd.C-nPr                                                      1824 6-Ph iPr C.tbd.C-Et                                                       1825 6-Ph iPr C.tbd.C-3-Pyridyl                                                1826 6-Ph iPr C.tbd.C-2-furanyl                                                1827 6-Ph iPr C.tbd.C-3-furanyl                                                1828 6-Ph iPr C.tbd.C-2-thienyl                                                1829 6-Ph iPr C.tbd.C-3-thienyl                                                1830 6-Ph Et C.tbd.C-cycPr                                                     1831 6-Ph Et C.tbd.C-iPr                                                       1832 6-Ph Et C.tbd.C-nPr                                                       1833 6-Ph Et C.tbd.C-Et                                                        1834 6-CN cycPr C.tbd.C-cycPr                                                  1835 6-CN cycPr C.tbd.C-iPr                                                    1836 6-CN cycPr C.tbd.C-nPr                                                    1837 6-CN cycPr C.tbd.C-Et                                                     1838 6-CN cycPr C.tbd.C-3-Pyridyl                                              1839 6-CN cycPr C.tbd.C-2-furanyl                                              1840 6-CN cycPr C.tbd.C-3-furanyl                                              1841 6-CN cycPr C.tbd.C-2-thienyl                                              1842 6-CN cycPr C.tbd.C-3-thienyl                                              1843 6-CN iPr C.tbd.C-cycPr                                                    1844 6-CN iPr C.tbd.C-iPr                                                      1845 6-CN iPr C.tbd.C-iPr                                                      1846 6-CN iPr C.tbd.C-Et                                                       1847 6-CN iPr C.tbd.C-3-Pyridyl                                                1848 6-CN iPr C.tbd.C-2-furanyl                                                1849 6-CN iPr C.tbd.C-3-furanyl                                                1850 6-CN iPr C.tbd.C-2-thienyl                                                1851 6-CN iPr C.tbd.C-3-thienyl                                                1852 6-CN Et C.tbd.C-cycPr                                                     1853 6-CN Et C.tbd.C-iPr                                                       1854 6-CN Et C.tbd.C-nPr                                                       1855 6-CN Et C.tbd.C-Et                                                        1856 6-NO.sub.2 cycPr C.tbd.C-cycPr                                            1857 6-NO.sub.2 cycPr C.tbd.C-iPr                                              1858 6-NO.sub.2 cycPr C.tbd.C-nPr                                              1859 6-NO.sub.2 cycPr C.tbd.C-Et                                               1860 6-NO.sub.2 cycPr C.tbd.C-3-Pyridyl                                        1861 6-NO.sub.2 cycPr C.tbd.C-2-furanyl                                        1862 6-NO.sub.2 cycPr C.tbd.C-3-furanyl                                        1863 6-NO.sub.2 cycPr C.tbd.C-2-thienyl                                        1864 6-NO.sub.2 cycPr C.tbd.C-3-thienyl                                        1865 6-NO.sub.2 iPr C.tbd.C-cycPr                                              1866 6-NO.sub.2 iPr C.tbd.C-iPr                                                1867 6-NO.sub.2 iPr C.tbd.C-nPr                                                1868 6-NO.sub.2 iPr C.tbd.C-Et                                                 1869 6-NO.sub.2 iPr C.tbd.C-3-Pyridyl                                          1870 6-NO.sub.2 iPr C.tbd.C-2-furanyl                                          1871 6-NO.sub.2 iPr C.tbd.C-3-furanyl                                          1872 6-NO.sub.2 iPr C.tbd.C-2-thienyl                                          1873 6-NO.sub.2 iPr C.tbd.C-3-thienyl                                          1874 6-NO.sub.2 Et C.tbd.C-cycPr                                               1875 6-NO.sub.2 Et C.tbd.C-iPr                                                 1876 6-NO.sub.2 Et C.tbd.C-nPr                                                 1877 6-NO.sub.2 Et C.tbd.C-Et                                                  1878 6-NHMe cycPr C.tbd.C-cycPr                                                1879 6-NHMe cycPr C.tbd.C-iPr                                                  1880 6-NHMe cycPr C.tbd.C-nPr                                                  1881 6-NHMe cycPr C.tbd.C-Et                                                   1882 6-NHMe cycPr C.tbd.C-3-Pyridyl                                            1883 6-NHMe cycPr C.tbd.C-2-furanyl                                            1884 6-NHMe cycPr C.tbd.C-3-furanyl                                            1885 6-NHMe cycPr C.tbd.C-2-thienyl                                            1886 6-NHMe cycPr C.tbd.C-3-thienyl                                            1887 6-NHMe iPr C.tbd.C-cycPr                                                  1888 6-NHMe iPr C.tbd.C-iPr                                                    1889 6-NHMe iPr C.tbd.C-nPr                                                    1890 6-NHMe iPr C.tbd.C-Et                                                     1891 6-NHMe iPr C.tbd.C-3-Pyridyl                                              1892 6-NHMe iPr C.tbd.C-2-furanyl                                              1893 6-NHMe iPr C.tbd.C-3-furanyl                                              1894 6-NHMe iPr C.tbd.C-2-thienyl                                              1895 6-NHMe iPr C.tbd.C-3-thienyl                                              1896 6-NHMe Et C.tbd.C-cycPr                                                   1897 6-NHMe Et C.tbd.C-iPr                                                     1898 6-NHMe Et C.tbd.C-nPr                                                     1899 6-NHMe Et C.tbd.C-Et                                                      1900 6,7-diCl cycPr C.tbd.C-cycPr                                              1901 6,7-diCl cycPr C.tbd.C-nPr                                                1902 6,7-diCl cycPr C.tbd.C-Et                                                 1903 6,7-diCl cycPr C.tbd.C-3-Pyridyl                                          1904 6,7-diCl cycPr C.tbd.C-2-furanyl                                          1905 6,7-diCl cycPr C.tbd.C-3-furanyl                                          1906 6,7-diCl cycPr C.tbd.C-2-thienyl                                          1907 6,7-diCl cycPr C.tbd.C-3-thienyl                                          1908 6,7-diCl iPr C.tbd.C-cycPr                                                1909 6,7-diCl iPr C.tbd.C-nPr                                                  1910 6,7-diCl iPr C.tbd.C-Et                                                   1911 6,7-diCl iPr C.tbd.C-3-Pyridyl                                            1912 6,7-diCl iPr C.tbd.C-2-furanyl                                            1913 6,7-diCl iPr C.tbd.C-3-furanyl                                            1914 6,7-diCl iPr C.tbd.C-2-thienyl                                            1915 6,7-diCl iPr C.tbd.C-3-thienyl                                            1916 6,7-diCl Et C.tbd.C-cycPr                                                 1917 6,7-diCl Et C.tbd.C-iPr                                                   1918 6,7-diCl Et C.tbd.C-nPr                                                   1919 6,7-diCl Et C.tbd.C-Et                                                    1920 7-Cl cycPr C.tbd.C-nPr                                                    1921 7-Cl cycPr C.tbd.C-Et                                                     1922 7-Cl cycPr C.tbd.C-3-Pyridyl                                              1923 7-Cl cycPr C.tbd.C-2-furanyl                                              1924 7-Cl cycPr C.tbd.C-3-furanyl                                              1925 7-Cl cycPr C.tbd.C-2-thienyl                                              1926 7-Cl cycPr C.tbd.C-3-thienyl                                              1927 7-Cl iPr C.tbd.C-nPr                                                      1928 7-Cl iPr C.tbd.C-Et                                                       1929 7-Cl iPr C.tbd.C-3-Pyridyl                                                1930 7-Cl iPr C.tbd.C-2-furanyl                                                1931 7-Cl iPr C.tbd.C-3-furanyl                                                1932 7-Cl iPr C.tbd.C-2-thienyl                                                1933 7-Cl iPr C.tbd.C-3-thienyl                                                1934 7-Cl Et C.tbd.C-cycPr                                                     1935 7-Cl Et C.tbd.C-iPr                                                       1936 7-Cl Et C.tbd.C-nPr                                                       1937 7-Cl Et C.tbd.C-Et                                                      ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-)                        

                  TABLE 4                                                          ______________________________________                                           #STR45##                                                                       Ex. #  W       X      Y    Z    R.sup.1                                                                             R.sup.2                                 ______________________________________                                         2001 CH      CCl      CH   N    CF.sub.3                                                                            C.tbd.C-nPr                                 2002 CH CCl CH N CF.sub.3 C.tbd.C-Bu                                           2003 CH CCl CH N CF.sub.3 C.tbd.C-iBu                                          2004 CH CCl CH N CF.sub.3 C.tbd.C-tBu                                          2005 CH CCl CH N CF.sub.3 C.tbd.C-Et                                           2006 CH CCl CH N CF.sub.3 C.tbd.C-Me                                           2007 CH CCl CH N CF.sub.3 C.tbd.C-Ph                                           2008 CH CCl CH N CF.sub.3 C.tbd.C-2-Pyridyl                                    2009 CH CCl CH N CF.sub.3 C.tbd.C-3-Pyridyl                                    2010 CH CCl CH N CF.sub.3 C.tbd.C-4-Pyridyl                                    2011 CH CCl CH N CF.sub.3 C.tbd.C-2-furanyl                                    2012 CH CCl CH N CF.sub.3 C.tbd.C-3-furanyl                                    2013 CH CCl CH N CF.sub.3 C.tbd.C-2-thienyl                                    2014 CH CCl CH N CF.sub.3 C.tbd.C-3-thienyl                                    2015 CH CCl CH N CF.sub.3 CH═CH-cycPr                                      2016 CH CCl CH N CF.sub.3 CH═CH-iPr                                        2017 CH CCl CH N CF.sub.3 CH═CH-nPr                                        2018 CH CCl CH N CF.sub.3 CH═CH-Bu                                         2019 CH CCl CH N CF.sub.3 CH═CH-iBu                                        2020 CH CCl CH N CF.sub.3 CH═CH-tBu                                        2021 CH CCl CH N CF.sub.3 CH═CH-Et                                         2022 CH CCl CH N CF.sub.3 CH═CH-Me                                         2023 CH CCl CH N CF.sub.3 CH═CH-Ph                                         2024 CH CCl CH N CF.sub.3 CH═CH-2-Pyridyl                                  2025 CH CCl CH N CF.sub.3 CH═CH-3-Pyridyl                                  2026 CH CCl CH N CF.sub.3 CH═CH-4-Pyridyl                                  2027 CH CCl CH N CF.sub.3 CH═CH-2-furanyl                                  2028 CH CCl CH N CF.sub.3 CH═CH-3-furanyl                                  2029 CH CCl CH N CF.sub.3 CH═CH-2-thienyl                                  2030 CH CCl CH N CF.sub.3 CH═CH-3-thienyl                                  2031 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2032 CH CCl CH N CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2033 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2034 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2035 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2036 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2037 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2038 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2039 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2040 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2041 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2042 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2043 CH CCl CH N CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2044 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-cycPr                               2045 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-iPr                                 2046 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-nPr                                 2047 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Bu                                  2048 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-iBu                                 2049 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-tBu                                 2050 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Et                                  2051 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Me                                  2052 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-Ph                                  2053 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-Pyridyl                           2054 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-Pyridyl                           2055 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-4-Pyridyl                           2056 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-furanyl                           2057 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-furanyl                           2058 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-2-thienyl                           2059 CH C(OCH.sub.3) CH N CF.sub.3 C.tbd.C-3-thienyl                           2060 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-cycPr                             2061 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-iPr                               2062 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-nPr                               2063 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Bu                                2064 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-iBu                               2065 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-tBu                               2066 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Et                                2067 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Me                                2068 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-Ph                                2069 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-Pyridyl                         2070 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-Pyridyl                         2071 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-4-Pyridyl                         2072 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-furanyl                         2073 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-furanyl                         2074 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-2-thienyl                         2075 CH C(OCH.sub.3) CH N CF.sub.3 CH═CH-3-thienyl                         2076 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2077 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2078 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2079 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2080 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2081 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2082 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2083 CH C(OCH.sub.3) CH N CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2084 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2085 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2086 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2087 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2088 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2089 CH C(OCH.sub.3) CH N CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2090 CH CH CH N CF.sub.3 C.tbd.C-cyc                                          Pr                                          2091 CH CH CH N CF.sub.3 C.tbd.C-iPr                                           2092 CH CH CH N CF.sub.3 C.tbd.C-nPr                                           2093 CH CH CH N CF.sub.3 C.tbd.C-Et                                            2094 CH CH CH N CF.sub.3 C.tbd.C-3-Pyridyl                                     2095 CH CH CH N CF.sub.3 C.tbd.C-2-furanyl                                     2096 CH CH CH N CF.sub.3 C.tbd.C-3-furanyl                                     2097 CH CH CH N CF.sub.3 C.tbd.C-2-thienyl                                     2098 CH CH CH N CF.sub.3 C.tbd.C-3-thienyl                                     2099 CH CCl N CH CF.sub.3 C.tbd.C-iPr                                          2100 CH CCl N CH CF.sub.3 C.tbd.C-nPr                                          2101 CH CCl N CH CF.sub.3 C.tbd.C-Bu                                           2102 CH CCl N CH CF.sub.3 C.tbd.C-iBu                                          2103 CH CCl N OH CF.sub.3 C.tbd.C-tBu                                          2104 CH CCl N CH CF.sub.3 C.tbd.C-Et                                           2105 CH CCl N CH CF.sub.3 C.tbd.C-Me                                           2106 CH CCl N CH CF.sub.3 C.tbd.C-Ph                                           2107 CH CCl N CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2108 CH CCl N CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2109 CH CCl N CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2110 CH CCl N CH CF.sub.3 C.tbd.C-2-furanyl                                    2111 CH CCl N CH CF.sub.3 C.tbd.C-3-furanyl                                    2112 CH CCl N CH CF.sub.3 C.tbd.C-2-thienyl                                    2113 CH CCl N CH CF.sub.3 C.tbd.C-3-thienyl                                    2114 CH CCl N CH CF.sub.3 CH═CH-cycPr                                      2115 CH CCl N CH CF.sub.3 CH═CH-iPr                                        2116 CH CCl N CH CF.sub.3 CH═CH-nPr                                        2117 CH CCl N CH CF.sub.3 CH═CH-Bu                                         2118 CH CCl N CH CF.sub.3 CH═CH-iBu                                        2119 CH CCl N CH CF.sub.3 CH═CH-tBu                                        2120 CH CCl N CH CF.sub.3 CH═CH-Et                                         2121 CH CCl N CH CF.sub.3 CH═CH-Me                                         2122 CH CCl N CH CF.sub.3 CH═CH-Ph                                         2123 CH CCl N CH CF.sub.3 CH═CH-2-Pyridyl                                  2124 CH CCl N CH CF.sub.3 CH═CH-3-Pyridyl                                  2125 CH CCl N CH CF.sub.3 CH═CH-4-Pyridyl                                  2126 CH CCl N CH CF.sub.3 CH═CH-2-furanyl                                  2127 CH CCl N CH CF.sub.3 CH═CH-3-furanyl                                  2128 CH CCl N CH CF.sub.3 CH═CH-2-thienyl                                  2129 CH CCl N CH CF.sub.3 CH═CH-3-thienyl                                  2130 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2131 CH CCl N CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2132 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2133 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2134 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2135 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2136 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2137 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2138 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2139 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2140 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2141 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2142 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2143 CH CCl N CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2144 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-iPr                                 2145 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-nPr                                 2146 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Bu                                  2147 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-iBu                                 2148 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-tBu                                 2149 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Et                                  2150 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Me                                  2151 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-Ph                                  2152 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-Pyridyl                           2153 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-Pyridyl                           2154 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-4-Pyridyl                           2155 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-furanyl                           2156 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-furanyl                           2157 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-2-thienyl                           2158 CH C(OCH.sub.3) N CH CF.sub.3 C.tbd.C-3-thienyl                           2159 CH C(CCH.sub.3) N CH CF.sub.3 CH═CH-cycPr                             2160 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-iPr                               2161 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-nPr                               2162 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Bu                                2163 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-iBu                               2164 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-tBu                               2165 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Et                                2166 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Me                                2167 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-Ph                                2168 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-Pyridyl                         2169 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-3-Pyridyl                         2170 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-4-Pyridyl                         2171 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-furanyl                         2172 CH C(CCH.sub.3) N CH CF.sub.3 CH═CH-3-furanyl                         2173 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-2-thienyl                         2174 CH C(OCH.sub.3) N CH CF.sub.3 CH═CH-3-thienyl                         2175 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2176 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2177 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2178 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2179 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2180 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2181 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2182 CH C(OCH.sub.3) N CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2183 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2184 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2185 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2186 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2187 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2188 CH C(OCH.sub.3) N CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2189 CH CH N CH CF.sub.3 C.tbd.C-cyc                                          Pr                                          2190 CH CH N CH CF.sub.3 C.tbd.C-iPr                                           2191 CH CH N CH CF.sub.3 C.tbd.C-nPr                                           2192 CH CH N CH CF.sub.3 C.tbd.C-Et                                            2193 CH CH N CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2194 CH CH N CH CF.sub.3 C.tbd.C-2-furanyl                                     2195 CH CH N CH CF.sub.3 C.tbd.C-3-furanyl                                     2196 CH CH N CH CF.sub.3 C.tbd.C-2-thienyl                                     2197 CH CH N CH CF.sub.3 C.tbd.C-3-thienyl                                     2198 CCl N CH CH CF.sub.3 C.tbd.C-cycPr                                        2199 CCl N CH CH CF.sub.3 C.tbd.C-iPr                                          2200 CCl N CH CH CF.sub.3 C.tbd.C-nPr                                          2201 CCl N CH CH CF.sub.3 C.tbd.C-Bu                                           2202 CCl N CH CH CF.sub.3 C.tbd.C-iBu                                          2203 CCl N CH CH CF.sub.3 C.tbd.C-tBu                                          2204 CCl N CH CH CF.sub.3 C.tbd.C-Et                                           2205 CCl N CH CH CF.sub.3 C.tbd.C-Me                                           2206 CCl N CH CH CF.sub.3 C.tbd.C-Ph                                           2207 CCl N CH CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2208 CCl N CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2209 CCl N CH CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2210 CCl N CH CH CF.sub.3 C.tbd.C-2-furanyl                                    2211 CCl N CH CH CF.sub.3 C.tbd.C-3-furanyl                                    2212 CCl N CH CH CF.sub.3 C.tbd.C-2-thienyl                                    2213 CCl N CH CH CF.sub.3 C.tbd.C-3-thienyl                                    2214 CCl N CH CH CF.sub.3 CH═CH-cycPr                                      2215 CCl N CH CH CF.sub.3 CH═CH-iPr                                        2216 CCl N CH CH CF.sub.3 CH═CH-nPr                                        2217 CCl N CH CH CF.sub.3 CH═CH-Bu                                         2218 CCl N CH CH CF.sub.3 CH═CH-iBu                                        2219 CCl N CH CH CF.sub.3 CH═CH-tBu                                        2220 CCl N CH CH CF.sub.3 CH═CH-Et                                         2221 CCl N CH CH CF.sub.3 CH═CH-Me                                         2222 CCl N CH CH CF.sub.3 CH═CH-Ph                                         2223 CCl N CH CH CF.sub.3 CH═CH-2-Pyridyl                                  2224 CCl N CH CH CF.sub.3 CH═CH-3-Pyridyl                                  2225 CCl N CH CH CF.sub.3 CH═CH-4-Pyridyl                                  2226 CCl N CH CH CF.sub.3 CH═CH-2-furanyl                                  2227 CCl N CH CH CF.sub.3 CH═CH-3-furanyl                                  2228 CCl N CH CH CF.sub.3 CH═CH-2-thienyl                                  2229 CCl N CH CH CF.sub.3 CH═CH-3-thienyl                                  2230 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2231 CCl N CH CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2232 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2233 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2234 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2235 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2236 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2237 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2238 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2239 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2240 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2241 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2242 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2243 CCl N CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2244 CH N CH CH CF.sub.3 C.tbd.C-iPr                                           2245 CH N CH CH CF.sub.3 C.tbd.C-nPr                                           2246 CH N CH CH CF.sub.3 C.tbd.C-Et                                            2247 CH N CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2248 CH N CH CH CF.sub.3 C.tbd.C-2-furanyl                                     2249 CH N CH CH CF.sub.3 C.tbd.C-3-furanyl                                     2250 CH N CH CH CF.sub.3 C.tbd.C-2-thienyl                                     2251 CH N CH CH CF.sub.3 C.tbd.C-3-thienyl                                     2252 N CCl CH CH CF.sub.3 C.tbd.C-cycPr                                        2253 N CCl CH CH CF.sub.3 C.tbd.C-iPr                                          2254 N CCl CH CH CF.sub.3 C.tbd.C-nPr                                          2255 N CCl CH CH CF.sub.3 C.tbd.C-Bu                                           2256 N CCl CH CH CF.sub.3 C.tbd.C-iBu                                          2257 N CCl CH CH CF.sub.3 C.tbd.C-tBu                                          2258 N CCl CH CH CF.sub.3 C.tbd.C-Et                                           2259 N CCl CH CH CF.sub.3 C.tbd.C-Me                                           2260 N CCl CH CH CF.sub.3 C.tbd.C-Ph                                           2261 N CCl CH CH CF.sub.3 C.tbd.C-2-Pyridyl                                    2262 N CCl CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                    2263 N CCl CH CH CF.sub.3 C.tbd.C-4-Pyridyl                                    2264 N CCl CH CH CF.sub.3 C.tbd.C-2-furanyl                                    2265 N CCl CH CH CF.sub.3 C.tbd.C-3-furanyl                                    2266 N CCl CH CH CF.sub.3 C.tbd.C-2-thienyl                                    2267 N CCl CH CH CF.sub.3 C.tbd.C-3-thienyl                                    2268 N CCl CH CH CF.sub.3 CH═CH-cycPr                                      2269 N CCl CH CH CF.sub.3 CH═CH-iPr                                        2270 N CCl CH CH CF.sub.3 CH═CH-nPr                                        2271 N CCl CH CH CF.sub.3 CH═CH-Bu                                         2272 N CCl CH CW CF.sub.3 CH═CH-iBu                                        2273 N CCl CH CH CF.sub.3 CH═CH-tBu                                        2274 N CCl CH CH CF.sub.3 CH═CH-Et                                         2275 N CCl CH CH CF.sub.3 CH═CH-Me                                         2276 N CCl CH CH CF.sub.3 CH═CH-Ph                                         2277 N CCl CH CH CF.sub.3 CH═CH-2-Pyridyl                                  2278 N CCl CH CH CF.sub.3 CH═CH-3-Pyridyl                                  2279 N CCl CH CH CF.sub.3 CH═CH-4-Pyridyl                                  2280 N CCl CH CH CF.sub.3 CH═CH-2-furanyl                                  2281 N CCl CH CH CF.sub.3 CH═CH-3-furanyl                                  2282 N CCl CH CH CF.sub.3 CH═CH-2-thienyl                                  2283 N CCl CH CH CF.sub.3 CH═CH-3-thienyl                                  2284 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2285 N CCl CH CH CF.sub.3 CH.sub.2                                            CH.sub.2 CH(CH.sub.3).sub.2                 2286 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                  2287 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.3                           2288 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                             2289 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                               2290 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                                2291 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                         2292 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-Pyridyl                         2293 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -4-Pyridyl                         2294 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-furanyl                         2295 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-furanyl                         2296 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-thienyl                         2297 N CCl CH CH CF.sub.3 CH.sub.2 CH.sub.2 -3-thienyl                         2298 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-cycPr                               2299 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-iPr                                 2300 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-nPr                                 2301 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Bu                                  2302 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-iBu                                 2303 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-tBu                                 2304 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Et                                  2305 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Me                                  2306 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-Ph                                  2307 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-Pyridyl                           2308 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-Pyridyl                           2309 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-4-Pyridyl                           2310 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-furanyl                           2311 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-furanyl                           2312 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-2-thienyl                           2313 N C(OCH.sub.3) CH CH CF.sub.3 C.tbd.C-3-thienyl                           2314 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-cycPr                             2315 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-iPr                               2316 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-nPr                               2317 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Bu                                2318 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-iBu                               2319 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-tBu                               2320 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Et                                2321 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Me                                2322 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-Ph                                2323 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-Pyridyl                         2324 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-Pyridyl                         2325 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-4-Pyridyl                         2326 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-furanyl                         2327 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-furanyl                         2328 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-2-thienyl                         2329 N C(OCH.sub.3) CH CH CF.sub.3 CH═CH-3-thienyl                         2330 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                                            CH.sub.3                                    2331 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH(CH.sub.3).sub.2        2332 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3                                             2333 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 CH.sub.3                  2334 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -cycPr                    2335 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -tBu                      2336 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -Ph                       2337 N C(OCH.sub.3) CH CH CF.sub.3 CH.sub.2 CH.sub.2 -2-Pyridyl                                                    2338 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-Pyridyl                                                    2339 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -4-Pyridyl                                                    2340 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-furanyl                                                    2341 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-furanyl                                                    2342 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -2-thienyl                                                    2343 N C(OCH.sub.3) CH CH CF.sub.3                                            CH.sub.2 CH.sub.2 -3-thienyl                                                    2344 N CH CH CH CF.sub.3 C.tbd.C-cyc                                          Pr                                          2345 N CH CH CH CF.sub.3 C.tbd.C-iPr                                           2346 N CH CH CH CF.sub.3 C.tbd.C-nPr                                           2347 N CH CH CH CF.sub.3 C.tbd.C-Et                                            2348 N CH CH CH CF.sub.3 C.tbd.C-3-Pyridyl                                     2349 N CH CH CH CF.sub.3 C.tbd.C-2-furanyl                                     2350 N CH CH CH CF.sub.3 C.tbd.C-3-furanyl                                     2351 N CH CH CH CF.sub.3 C.tbd.C-2-thienyl                                     2352 N CH CH CH CF.sub.3 C.tbd.C-3-thienyl                                   ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-).                       

                  TABLE 5                                                          ______________________________________                                           #STR46##                                                                        -                               m.p.                                          Ex. G R.sup.1 R.sup.2 (° C.) Mass Spec                                ______________________________________                                         2401 6-Cl   cycPr     C.tbd.C-Et 137-138.5                                       2402 6-Cl CF.sub.3 C.tbd.C-Et 178                                              2403 6-Cl Et C.tbd.C-Et 175-176                                                2404 6-Cl CH.sub.3 CH.sub.3 202 212.0440                                       2405 6-Cl CH.sub.3 C.tbd.C-cycPr 184                                           2406 6-Cl CH.sub.3 CH.sub.3 221-222 228.0262                                   2407 6-Cl CH.sub.3 C.tbd.C-iPr 168 264.0790                                    2408 6-Cl CF.sub.3 CH═CH-cycPr(cis)                                        2409 6-Cl CF.sub.3 C.tbd.C-iPr 167-168                                         2410 6-Cl CF.sub.3 CH═CH-iPr(cis) 146-147                                  2411 6-Cl CF.sub.3 CH.sub.2 CH.sub.2 -iPr 129-131                              2412 6-Cl CF.sub.3 C.tbd.C-iPr 116-118                                         2413 6-Cl CF.sub.3 CH═CH-iPr(trans) 127-129                                2414 6-Cl OMe CH.sub.2 CH.sub.2 -Ph  318.0897                                  2415 6-Cl OEt Ph  304 (MH.sup.+)                                               2416 6-Cl CF.sub.3 C.tbd.C-1-d-cycPr 180-181 317.0406                          2417 6-Cl CF.sub.3 C.tbd.C-1-d-cycPr 133-134 317.0417                          2418 6-Cl CF.sub.3 C.tbd.C-1-Me-cycPr 158-159 347.0785                         2419 6-Cl CF.sub.3 Butyl 135-136                                               2420 6-Cl CF.sub.3 C.tbd.C-cycBu 183-185 330.0495                              2421 6-Cl CF.sub.3 C(Me).sub.2 CC.tbd.CCH                                      2422 6-Cl CF.sub.3 CF.sub.3 148-149                                            2423 6-Cl CF.sub.3 C.tbd.C--CF.sub.3 155-156                                   2424 6-Cl CF.sub.3 Pentyl                                                      2425 6-Cl CF.sub.3 C.tbd.C-Ph  352.0353                                        2426 6-Cl CF.sub.3 C.tbd.C-3-py                                                2427 6-Cl CF.sub.3 C.tbd.C-2-thiazole                                          2428 6-Cl CF.sub.3 NH-iBu 182-183                                              2429 6-Cl CF.sub.3 C.tbd.C-4-py                                                2430 6-Cl CH.sub.3 C.tbd.C-Ph 181-182 298.0620                                 2431 6-Cl iPr C.tbd.C-iPr oil 292.1106                                         2432 6-Cl iPr C.tbd.C-iBu oil 306.1268                                         2433 6-Cl iPr C.tbd.C-cycPr amorphous 290.0938                                 2434 6-Cl iPr C.tbd.C-Ph 177-178 326.0955                                      2435 6-Cl Et C.tbd.C-cycPr 183-184 276.0792                                    2436 6-Cl Et C.tbd.C-iPr 143-144 278.0958                                      2437 6-Cl Et C.tbd.C-Ph 165-166 312.0790                                       2438 6-Cl Et C.tbd.C-iBu 136-137 292.1100                                      2439 6-Cl cycPr C.tbd.C-cycPr 142-143 288.0789                                 2440 6-Cl cycPr C.tbd.C-iPr 152-153 290.0950                                   2441 6-Cl cycPr C.tbd.C-Ph 156-157 324.0778                                    2442 6-Cl cycPr C.tbd.C-iBu 142-143 304.1102                                   2443 6-Cl iPr CH.sub.2 CH.sub.2 -iPr oil 296.1417                              2444 6-Cl cycPr CH.sub.2 CH.sub.2 CH═CH.sub.2 oil 278.0946                 2445 6-Cl C.tbd.C-cycPr C.tbd.C-cycPr 129-131 312.0786                         2446 6-Cl CF.sub.3 C.tbd.C-iBu 176-177 332.0664                                2447 6-Cl C.tbd.C-iPr C.tbd.C-iPr 139 316.1104                                 2448 6-Cl iPr CH.sub.2 CH.sub.2 CH═CH.sub.2 oil 280.1109                   2449 6-Cl C.tbd.CH C.tbd.C-iPr 161-162 274.0638                                2450 6-Cl CF.sub.3 C(Me).sub.2 CH═CH.sub.2 113-114 320.0662                                                       2451 6-Cl CF.sub.3 C.tbd.C-2-Py                                                2452 6-Cl CF.sub.3 C.tbd.C-nPr                                                193-194 318.0500                              (MH.sup.+)                                                                2453 6-Cl CF.sub.3 C.tbd.C-1-OH-cycPr                                          2454 6-Cl C.tbd.CH C.tbd.C-Et 157-159 260.0483                                 2455 6-Cl CF.sub.3 CH.sub.2 -iPr 177-178 308.0659                              2456 6-Cl iPr CH.sub.2 -iPr 132-133 282.1261                                   2457 6-Cl cycPr CH.sub.2 -iPr 136-137 280.1104                                 2458 6-Cl iPr C.tbd.C-Et amorphous                                             2459 6-Cl CF.sub.3 C.tbd.C-Et 142-146                                          2460 6-Cl CF.sub.3 C.tbd.C-Et 143-147                                          2461 6-Cl CF.sub.3 CH.sub.2 CH.sub.2 -iPr amorphous                            2462 6-Cl CF.sub.3 CH.sub.2 CH.sub.2 -iPr amorphous                            2463 6-Cl iPr C.tbd.C-cycPr amorphous                                          2464 6-Cl iPr C.tbd.C-cycPr amorphous                                          2465 6-Cl CF.sub.3 CH.sub.2 --C.tbd.C-Me 196-199                               2466 6-Cl CF.sub.3 CH.sub.2 --C.tbd.C-Et 140-145                               2467 6-Cl CF.sub.3 NHCH.sub.2 CH.sub.2 CH.sub.3 184-185 309.0628                                                      2468 6-Cl CF.sub.3 C.tbd.C-2-fura                                             nyl 170-171                              2469 6-Cl CF.sub.3 C.tbd.C-3-thienyl 176.7-178                                 2470 6-Cl CF.sub.3 C.tbd.C-3-furanyl 155-156                                   2471 6-Cl CF.sub.3 OBu 132-133                                                 2472 6-Cl CF.sub.3 C.tbd.C-5-thiazolyl 196-196.5                               2473 6-Cl CF.sub.3 CH═CH-3-Py(t) 188-189                                   2474 6-Cl CF.sub.3 C.tbd.C-3-py 183.5                                          2475 6-Cl CF.sub.3 C.tbd.C-3-py                                                2476 6-Cl CF.sub.3 CH═CH-iPr(t)                                            2477 6-Cl CF.sub.3 CH═CH-iPr(t)                                            2478 6-Cl CF.sub.3 OCH.sub.2 CH.sub.2 -iPr  338.0766                           2479 6-Cl CF.sub.3 OCH.sub.2 CH.sub.2 --OMe 127-128 326.0391                   2480 6-Cl CF.sub.3 CH═CH-cycPr(t) 136-137                                  2481 6-Cl CF.sub.3 CH═CH-cycPr(t) amorphous                                2482 6-Cl CF.sub.3 CH═CH-cycPr(t) amorphous                                2483 6-Cl CF.sub.3 CH═CH-nPr(t) 127-128                                    2484 6-Cl CF.sub.3 CH═CH-Et(t) 146-147                                     2485 6-Cl CF.sub.3 C.tbd.C-Me 243-244                                          2486 6-Cl CF.sub.3 C.tbd.C-iPr 116-118                                         2487 6-F iPr C.tbd.C-iPr  276.1400                                             2488 6-F iPr C.tbd.C-cycPr  274.1243                                           2489 6-F CF.sub.3 C.tbd.C-iPr  302.0797                                        2490 6-F CF.sub.3 CH.sub.2 CH.sub.2 -iPr  306.1111                             2491 6-F CF.sub.3 C.tbd.C-cycPr  300.0638                                      2492 6-F CF.sub.3 C.tbd.C-Ph  336.0648                                         2493 6-F CF.sub.3 Pentyl  306.1106                                             2494 6-F OF.sub.3 C.tbd.C-iPr                                                  2495 6-F CF.sub.3 C.tbd.C-iPr  302.0792                                        2496 6-F CF.sub.3 C.tbd.C-Et  288.0650                                              (MH.sup.+)                                                                2497 6-F OF.sub.3 C.tbd.C-nPr  302.0796                                        2498 6-F CF.sub.3 Butyl  292.0947                                            ______________________________________                                          *Unless otherwise noted, stereochemistry is (+/-).                       

Utility

The compounds of this invention possess reverse transcriptase inhibitory activity, in particular, HIV inhibitory efficacy. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are therefore useful as antiviral agents for the treatment of HIV infection and associated diseases. The compounds of formula (I) possess HIV reverse transcriptase inhibitory activity and are effective as inhibitors of HIV growth. The ability of the compounds of the present invention to inhibit viral growth or infectivity is demonstrated in standard assay of viral growth or infectivity, for example, using the assay described below.

The compounds of formula (I) of the present invention are also useful for the inhibition of HIV in an ex vivo sample containing HIV or expected to be exposed to HIV. Thus, the compounds of the present invention may be used to inhibit HIV present in a body fluid sample (for example, a serum or semen sample) which contains or is suspected to contain or be exposed to HIV.

The compounds provided by this invention are also useful as standard or reference compounds for use in tests or assays for determining the ability of an agent to inhibit viral clone replication and/or HIV reverse transcriptase, for example in a pharmaceutical research program. Thus, the compounds of the present invention may be used as a control or reference compound in such assays and as a quality control standard. The compounds of the present invention may be provided in a commercial kit or container for use as such standard or reference compound.

Since the compounds of the present invention exhibit specificity for HIV reverse transcriptase, the compounds of the present invention may also be useful as diagnostic reagents in diagnostic assays for the detection of HIV reverse transcriptase. Thus, inhibition of the reverse transcriptase activity in an assay (such as the assays described herein) by a compound of the present invention would be indicative of the presence of HIV reverse transcriptase and HIV virus.

As used herein "μg" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μL" denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μM" denotes micromolar, "mM" denotes millimolar, "M" denotes molar and "nm" denotes nanometer. "Sigma" stands for the Sigma-Aldrich Corp. of St. Louis, Mo.

HIV RNA Assay

DNA Plasmids and in vitro RNA transcripts:

Plasmid pDAB 72 containing both gag and pol sequences of BH10 (bp 113-1816) cloned into PTZ 19R was prepared according to Erickson-Viitanen et al. AIDS Research and Human Retroviruses 1989, 5, 577. The plasmid was linearized with Bam HI prior to the generation of in vitro RNA transcripts using the Riboprobe Gemini system II kit (Promega) with T7 RNA polymerase. Synthesized RNA was purified by treatment with RNase free DNAse (Promega), phenol-chloroform extraction, and ethanol precipitation. RNA transcripts were dissolved in water, and stored at -70° C. The concentration of RNA was determined from the A₂₆₀.

Probes:

Biotinylated capture probes were purified by HPLC after synthesis on an Applied Biosystems (Foster City, Calif.) DNA synthesizer by addition of biotin to the 5' terminal end of the oligonucleotide, using the biotin-phosphoramidite reagent of Cocuzza, Tet. Lett. 1989, 30, 6287. The gag biotinylated capture probe (5-biotin-CTAGCTCCCTGCTTGCCCATACTA 3') was complementary to nucleotides 889-912 of HXB2 and the pol biotinylated capture probe (5'-biotin-CCCTATCATTTTTGGTTTCCAT 3') was complementary to nucleotides 2374-2395 of HXB2. Alkaline phosphatase conjugated oligonucleotides used as reporter probes were prepared by Syngene (San Diego, Calif.). The pol reporter probe (5' CTGTCTTACTTTGATAAAACCTC 3') was complementary to nucleotides 2403-2425 of HXB2. The gag reporter probe (5' CCCAGTATTTGTCTACAGCCTTCT 3') was complementary to nucleotides 950-973 of HXB2. All nucleotide positions are those of the GenBank Genetic Sequence Data Bank as accessed through the Genetics Computer Group Sequence Analysis Software Package (Devereau Nucleic Acids Research 1984, 12, 387). The reporter probes were prepared as 0.5 μM stocks in 2×SSC (0.3 M NaCl, 0.03 M sodium citrate), 0.05 M Tris pH 8.8, 1 mg/mL BSA. The biotinylated capture probes were prepared as 100 μM stocks in water.

Streptavidin Coated Plates:

Streptavidin coated plates were obtained from Du Pont Biotechnology Systems (Boston, Mass.).

Cells and Virus Stocks:

MT-2 and MT-4 cells were maintained in RPMI 1640 supplemented with 5% fetal calf serum (FCS) for MT-2 cells or 10% FCS for MT-4 cells, 2 mM L-glutamine and 50 μg/mL gentamycin, all from Gibco. HIV-1 RF was propagated in MT-4 cells in the same medium. Virus stocks were prepared approximately 10 days after acute infection of MT-4 cells and stored as aliquots at -70° C. Infectious titers of HIV-1(RF) stocks were 1-3×10⁷ PFU (plaque forming units)/mL as measured by plaque assay on MT-2 cells (see below). Each aliquot of virus stock used for infection was thawed only once.

For evaluation of antiviral efficacy, cells to be infected were subcultured one day prior to infection. On the day of infection, cells were resuspended at 5×10⁵ cells/mL in RPMI 1640, 5% FCS for bulk infections or at 2×10⁶ /mL in Dulbecco's modified Eagles medium with 5% FCS for infection in microtiter plates. Virus was added and culture continued for 3 days at 37° C.

HIV RNA Assay:

Cell lysates or purified RNA in 3 M or 5 M GED were mixed with 5 M GED and capture probe to a final guanidinium isothiocyanate concentration of 3 M and a final biotin oligonucleotide concentration of 30 nM. Hybridization was carried out in sealed U bottom 96 well tissue culture plates (Nunc or Costar) for 16-20 hours at 37° C. RNA hybridization reactions were diluted three-fold with deionized water to a final guanidinium isothiocyanate concentration of 1 M and aliquots (150 μL) were transferred to streptavidin coated microtiter plates wells. Binding of capture probe and capture probe-RNA hybrid to the immobilized streptavidin was allowed to proceed for 2 hours at room temperature, after which the plates were washed 6 times with DuPont ELISA plate wash buffer (phosphate buffered saline(PBS), 0.05% Tween 20.) A second hybridization of reporter probe to the immobilized complex of capture probe and hybridized target RNA was carried out in the washed streptavidin coated well by addition of 120 μl of a hybridization cocktail containing 4×SSC, 0.66% Triton X 100, 6.66% deionized formamide, 1 mg/mL BSA and 5 nM reporter probe. After hybridization for one hour at 37° C., the plate was again washed 6 times. Immobilized alkaline phosphatase activity was detected by addition of 100 μL of 0.2 mM 4-methylumbelliferyl phosphate (MUBP, JBL Scientific) in buffer δ (2.5 M diethanolamine pH 8.9 (JBL Scientific), 10 mM MgCl₂, 5 mM zinc acetate dihydrate and 5 mM N-hydroxyethyl-ethylene-diamine-triacetic acid). The plates were incubated at 37° C. Fluorescence at 450 nM was measured using a microplate fluorometer (Dynateck) exciting at 365 nM.

Microplate Based Compound Evaluation in HIV-1 Infected MT-2 Cells:

Compounds to be evaluated were dissolved in DMSO and diluted in culture medium to twice the highest concentration to be tested and a maximum DMSO concentration of 2%. Further three-fold serial dilutions of the compound in culture medium were performed directly in U bottom microtiter plates (Nunc). After compound dilution, MT-2 cells (50 μL) were added to a final concentration of 5×10⁵ per mL (1×10⁵ per well). Cells were incubated with compounds for 30 minutes at 37° C. in a CO₂ incubator. For evaluation of antiviral potency, an appropriate dilution of HIV-1 (RF) virus stock (50 μL) was added to culture wells containing cells and dilutions of the test compounds. The final volume in each well was 200 μL. Eight wells per plate were left uninfected with 50 μL of medium added in place of virus, while eight wells were infected in the absence of any antiviral compound. For evaluation of compound toxicity, parallel plates were cultured without virus infection.

After 3 days of culture at 37° C. in a humidified chamber inside a CO₂ incubator, all but 25 μL of medium/well was removed from the HIV infected plates. Thirty seven μL of 5 M GED containing biotinylated capture probe was added to the settled cells and remaining medium in each well to a final concentration of 3 M GED and 30 nM capture probe. Hybridization of the capture probe to HIV RNA in the cell lysate was carried out in the same microplate well used for virus culture by sealing the plate with a plate sealer (Costar), and incubating for 16-20 hrs in a 37° C. incubator. Distilled water was then added to each well to dilute the hybridization reaction three-fold and 150 μL of this diluted mixture was transferred to a streptavidin coated microtiter plate. HIV RNA was quantitated as described above. A standard curve, prepared by adding known amounts of pDAB 72 in vitro RNA transcript to wells containing lysed uninfected cells, was run on each microtiter plate in order to determine the amount of viral RNA made during the infection.

In order to standardize the virus inoculum used in the evaluation of compounds for antiviral activity, dilutions of virus were selected which resulted in an IC₉₀ value (concentration of compound required to reduce the HIV RNA level by 90%) for dideoxycytidine (ddC) of 0.2 μg/mL. IC₉₀ values of other antiviral compounds, both more and less potent than ddC, were reproducible using several stocks of HIV-1 (RF) when this procedure was followed. This concentration of virus corresponded to ˜3×10⁵ PFU (measured by plague assay on MT-2 cells) per assay well and typically produced approximately 75% of the maximum viral RNA level achievable at any virus inoculum. For the HIV RNA assay, IC₉₀ values were determined from the percent reduction of net signal (signal from infected cell samples minus signal from uninfected cell samples) in the RNA assay relative to the net signal from infected, untreated cells on the same culture plate (average of eight wells). Valid performance of individual infection and RNA assay tests was judged according to three criteria. It was required that the virus infection should result in an RNA assay signal equal to or greater than the signal generated from 2 ng of pDAB 72 in vitro RNA transcript. The IC₉₀ for ddC, determined in each assay run, should be between 0.1 and 0.3 μg/mL. Finally, the plateau level of viral RNA produced by an effective reverse transcriptase inhibitor should be less than 10% of the level achieved in an uninhibited infection. A compound was considered active if its IC₉₀ was found to be less than 20 μM.

For antiviral potency tests, all manipulations in microtiter plates, following the initial addition of 2× concentrated compound solution to a single row of wells, were performed using a Perkin Elmer/Cetus ProPette.

HIV-1 RT Assay Materials and Methods

This assay measures HIV-1 RT RNA dependent DNA polymerase activity by the incorporation of 3H dTMP onto the template primer Poly (rA) oligo (dT)12-18. The template primer containing the incorporated radioactivity was separated from unincorporated label by one of two methods:

Method 1. The template primer was precipitated with TCA, collected on glass fiber filters and counted for radioactivity with a scintillation counter.

Method 2. The currently used method is more rapid and convenient. The template primer is captured on an diethyl amino ethyl (DEAE) ion exchange membrane which is then counted for radioactivity after washing off the free nucleotide.

Materials and Reagents:

The template primer Poly (rA) oligo (dT)12-18 and dTTP were purchased from Pharmacia Biotech. The template primer and nucleotide were dissolved in diethyl pyrocarbonate water to a concentration of 1 mg/ml and 5.8 mM respectively. The substrates were aliquoted (template primer at 20 μl/aliquot, dTTP at 9 μl/aliquot) and frozen at -20° C.

The 3H dTTP (2.5 mCi/ml in 10 mM Tricine at pH 7.6; specific activity of 90-120 Ci/mmol) and the recombinant HIV-1 Reverse Transcriptase (HxB2 background; 100 U/10 μl in 100 mM potassium phosphate at pH 7.1, 1 mM dithiothreitol and 50% glycerol) were purchased from DuPont NEN. 1 Unit of enzyme is defined by DuPont NEN as the amount required to incorporate 1 nmol of labelled dTTP into acid-insoluble material in 10 minutes at 37° C. The 3H dTTP was aliquoted at 23.2 μl/microfuge tube (58 μCi) and frozen at -20° C. The HIV-1 Reverse Transcriptase (RT) was diluted 10 fold with RT buffer (80 mM KCl, 50 mM Tris HCl, 12 mM MgCl2, 1 mM DTT, 50 μM EGTA, 5 mg/ml BSA, 0.01% Triton-X 100, pH 8.2) and aliquoted at 10 μl/microfuge tube (10 Units/10 μl). One aliquot (enough for 8 assays) was diluted further to 10 Units/100 μl and aliquoted into 8 tubes (1.25 Units/12.5 μl ). All aliquots were frozen at -70° C.

The Millipore Multiscreen DE 96 well filter plates, multiscreen plate adaptors, and microplate press-on adhesive sealing film were purchased from Millipore. The filter plate containing 0.65 μm pore size diethyl amino ethyl cellulose (DEAE) paper disks was pretreated with 0.3 M ammonium formate and 10 mM sodium pyrophosphate (2 times 200 μl/well) at pH 8.0 prior to use. A Skatron 96 well cell harvester and glass fiber filter mats were purchased from Skatron Instruments. Microscint 20 scintillation cocktail was purchased from Packard. Beckman Ready Flow III scintillation cocktail was purchased from Beckman.

HIV-1 RT Assay:

The enzyme and substrate mixture were freshly prepared from the above stock solutions. 1.25 Units of enzyme was diluted with RT buffer (containing 5 mg/ml BSA) to a concentration of 0.05 Units/10 μl or 0.7 nM. Final enzyme and BSA concentrations in the assay were 0.01 Units or 0.14 nM and 1 mg/ml respectively. The inhibitor and substrate mixture were diluted with RT buffer containing no BSA. All inhibitors were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 3 mM and stored at -20 ° C. after use. A Biomek robot was used to dilute the inhibitors in a 96 well plate. Inhibitors were initially diluted 96 fold from stock and then serially diluted two times (10 fold/dilution) from 31.25 μM to 312.5 nM and 312.5 nM. Depending on the potency of the inhibitor, one of the three dilutions was further diluted. Typically the highest concentration (31.25 μM) was serially diluted three times at 5 fold/dilution to 6.25, 1.25, and 0.25 μM. Final inhibitor concentrations in the assay were 12.5, 2.5, 0.5, and 0.1 μM. For potent inhibitors of HIV-1 RT, the final inhibitor concentrations used were 0.1 or 0.01 that stated above. The substrate mixture contained 6.25 μg/ml of Poly (rA) oligo (dT)12-18 and 12.5 μM of dTTP (58 μCi 3H dTTP). The final substrate concentrations were 2.5 μg/ml and 5 μM respectively.

Using the Beckman Instruments Biomek robot, 10 μl of HIV-1 RT was combined with 20 μl of inhibitor in a 96 well U bottom plate. The enzyme and inhibitor were preincubated at ambient temperature for 6 minutes. 20 μl of the substrate mixture was added to each well to initiate the reaction (total volume was 50 μl). The reactions were incubated at 37 C and terminated after 45 minutes.

For method 1, 200 μl of an ice-cold solution of 13% trichloroacetic acid (TCA) and 10 mM sodium pyrophosphate was added to each of the 96 wells. The 96 well plate was then placed in an ice-water bath for 30 minutes. Using A Skatron 96 well cell harvester, the acid precipitable material was collected on a glass fiber filter mat that had been presoaked in 13% TCA and 10 mM sodium pyrophosphate. The filter disks were washed 3 times (2.0 ml/wash) with 1 N HCl and 10 mM sodium pyrophosphate. The filter disks were punched out into scintillation vials, 2.0 ml of Beckman Ready Flow III scintillant was added, and the vials were counted for radioactivity for 1 minute.

For method 2, the assay was terminated with the addition of 175 μl/well of 50 mM EDTA at pH 8.0. Then 180 μl of the mixture was transferred to a pretreated Millipore DE 96 well filter plate. Vacuum was applied to the filter plate to aspirate away the liquid and immobilize the template primer on the DEAE filter disks. Each well was washed 3 times with 200 μl of 0.3 M ammonium formate and 10 mM sodium pyrophosphate at pH 8.0. 50 μl of microscint 20 scintillation cocktail was added to each well and the plate was counted for radioactivity on a Packard Topcount at 1 minute/well.

The IC₅₀ values are calculated with the equation:

    IC.sub.50 =[Inh]/(1/fractional activity-1)

where the fractional activity=RT activity (dpms) in the presence of inhibitor/RT activity (dpms) in the absence of inhibitor. For a given inhibitor, the IC₅₀ values were calculated for the inhibitor concentrations that range between 0.1-0.8 fractional activity. The IC₅₀ values in this range (generally 2 values) were averaged. A compound was considered active if its IC₅₀ was found to be less than 12 μM.

Protein Binding and Mutant Resistance

In order to characterize NNRTI analogs for their clinical efficacy potential the effect of plasma proteins on antiviral potency and measurements of antiviral potency against wild type and mutant variants of HIV which carry amino acid changes in the known binding site for NNRTIs were examined. The rationale for this testing strategy is two fold:

1. Many drugs are extensively bound to plasma proteins. Although the binding affinity for most drugs for the major components of human plasma, namely, human serum albumin (HSA) or alpha-1-acid glycoprotein (AAG), is low, these major components are present in high concentration in the blood. Only free or unbound drug is available to cross the infected cell membrane for interaction with the target site (i.e., HIV-1 reverse transcriptase, HIV-1 RT). Therefore, the effect of added HSA+AAG on the antiviral potency in tissue culture more closely reflects the potency of a given compound in the clinical setting. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. The fold increase in apparent IC90 for test compounds in the presence or added levels of HSA and AAG that reflect in vivo concentrations (45 mg/ml HSA, 1 mg/ml AAG) was then calculated. The lower the fold increase, the more compound will be available to interact with the target site.

2. The combination of the high rate of virus replication in the infected individual and the poor fidelity of the viral RT results in the production of a quasi-species or mixtures of HIV species in the infected individual. These species will include a majority wild type species, but also mutant variants of HIV and the proportion of a given mutant will reflect its relative fitness and replication rate. Because mutant variants including mutants with changes in the amino acid sequence of the viral RT likely pre-exist in the infected individual's quasi-species, the overall potency observed in the clinical setting will reflect the ability of a drug to inhibit not only wild type HIV-1, but mutant variants as well. We thus have constructed, in a known genetic background, mutant variants of HIV-1 which carry amino acid substitutions at positions thought to be involved in NNRTI binding, and measured the ability of test compounds to inhibit replication of these mutant viruses. The concentration of compound required for 90% inhibition of virus replication as measured in a sensitive viral RNA-based detection method is designated the IC90. It is desirable to have a compound which has high activity against a variety of mutants.

Dosage and Formulation

The antiviral compounds of this invention can be administered as treatment for viral infections by any means that produces contact of the active agent with the agent's site of action, i.e., the viral reverse transcriptase, in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules can be prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearic.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil can be prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules should then be washed and dried.

Tablets

A large number of tablets can be prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

Suspension

An aqueous suspension can be prepared for oral administration so that each 5 mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of vanillin.

Injectable

A parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

Combination of Components (a) and (b)

Each therapeutic agent component of this invention can independently be in any dosage form, such as those described above, and can also be administered in various ways, as described above. In the following description component (b) is to be understood to represent one or more agents as described previously. Thus, if components (a) and (b) are to be treated the same or independently, each agent of component (b) may also be treated the same or independently.

Components (a) and (b) of the present invention may be formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are not formulated together in a single dosage unit, the component (a) may be administered at the same time as component (b) or in any order; for example component (a) of this invention may be administered first, followed by administration of component (b), or they may be administered in the reverse order. If component (b) contains more that one agent, e.g., one RT inhibitor and one protease inhibitor, these agents may be administered together or in any order. When not administered at the same time, preferably the administration of component (a) and (b) occurs less than about one hour apart. Preferably, the route of administration of component (a) and (b) is oral. The terms oral agent, oral inhibitor, oral compound, or the like, as used herein, denote compounds which may be orally administered. Although it is preferable that component (a) and component (b) both be administered by the same route (that is, for example, both orally) or dosage form, if desired, they may each be administered by different routes (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously) or dosage forms.

As is appreciated by a medical practitioner skilled in the art, the dosage of the combination therapy of the invention may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

The proper dosage of components (a) and (b) of the present invention will be readily ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. By way of general guidance, typically a daily dosage may be about 100 milligrams to about 1.5 grams of each component. If component (b) represents more than one compound, then typically a daily dosage may be about 100 milligrams to about 1.5 grams of each agent of component (b). By way of general guidance, when the compounds of component (a) and component (b) are administered in combination, the dosage amount of each component may be reduced by about 70-80% relative to the usual dosage of the component when it is administered alone as a single agent for the treatment of HIV infection, in view of the synergistic effect of the combination.

The combination products of this invention may be formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component. In each formulation wherein contact is prevented between components (a) and (b) via a coating or some other material, contact may also be prevented between the individual agents of component (b).

Dosage forms of the combination products of the present invention wherein one active ingredient is enteric coated can be in the form of tablets such that the enteric coated component and the other active ingredient are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. Optionally, in order to further separate the two layers, one or more placebo layers may be present such that the placebo layer is between the layers of active ingredients. In addition, dosage forms of the present invention can be in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of microtablets, particles, granules or non-perils, which are then enteric coated. These enteric coated microtablets, particles, granules or non-perils are then placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time or concurrently by the same manner, will be readily apparent to those skilled in the art, based on the present disclosure.

Pharmaceutical kits useful for the treatment of HIV infection, which comprise a therapeutically effective amount of a pharmaceutical composition comprising a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers of materials may comprise separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein. 

What is claimed as new and desired to be secured by Letter Patent of United States is:
 1. A process for making a compound of formula Ia: ##STR47## or a stereoisomer or pharmaceutically acceptable salt form thereof, comprising:(a) contacting a nucleophile, R^(2b), with a compound of formula II: ##STR48## or stereoisomer thereof in a suitable solvent, wherein: R^(2b) is selected from R⁸ R⁷ CH--OH, R⁸ R⁷ CH--OM, R⁸ R⁷ CHNH₂, R⁸ R⁷ CHNH--M, R⁸ --C.tbd.C--M, R⁷ R⁸ C═CH--M, R⁸ R⁷ CH(CH₂)_(p) --M, R⁸ CH═CHC(H)(R⁷)--M, R⁸ R⁷ CHCH═CH--M;M is selected from Na, Li, Mg, Zn, Cu, Pd, Pt, Sn, Al, and B; A is O or S; W is N or CR³ ; X is N or CR⁴ ; Y is N or CR⁵ ; Z is N or CR⁶ ; provided that if two of W, X, Y, and Z are N, then the remaining are other than N; R^(1a) is selected from CF₃, CF₂ H, C₂ F₅, C₁₋₄ alkyl, C₃₋₅ cycloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl; R^(2a) is selected from --QCHR⁷ R⁸, --QCHR⁷ C.tbd.C--R⁸, --QCHR⁷ C═C--R⁸, --Q(CH₂)_(p) CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --(CH₂)_(p) CHR⁷ R⁸, --CHR⁷ C.tbd.C--R⁸, --CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I, C₁₋₃ alkoxy, and C₁₋₃ alkyl; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), NR⁷ C(O)OR^(7a), C(O)OR⁷, S(O)_(p) R⁷, SO₂ NHR⁷, NR⁷ SO₂ R^(7b), phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; alternatively, R³ and R⁴ together form --OCH₂ O--; R⁵ is selected from H, F, Cl, Br, and I; alternatively, R⁴ and R⁵ together form --OCH₂ O-- or a fused benzo ring; R⁶ is selected from H, OH, C₁₋₃ alkoxy, --CN, F, Cl, Br, I, NO₂, CF₃, CHO, C₁₋₃ alkyl, and C(O)NH₂ ; R⁷ is selected from H and C₁₋₃ alkyl; R^(7a) is selected from H and C₁₋₃ alkyl; R^(7b) is C₁₋₃ alkyl; R⁸ is selected from H, C₁₋₆ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₆ alkenyl, C₃₋₇ cycloalkyl substituted with 0-2 R⁹, phenyl substituted with 0-2 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-2 R¹⁰ ; R⁹ is selected from D, OH, C₁₋₃ alkoxy, C₁₋₃ alkyl, and F; R¹⁰ is selected from OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹ is selected from OR⁷, CN, F, Cl, Br, I, NO₂, NR⁷ R^(7a), CHO, C(O)CH₃, C(O)NH₂ ; Q is selected from O, S and NH; and, p is selected from 0, 1, and
 2. 2. The process according to claim 1, wherein:A is O; R^(1a) is selected from CF₃, CF₂ H, C₂ F₅ ; R^(2a) is selected from --OCHR⁷ R⁸, --OCH₂ C.tbd.C--R⁸, --OCH₂ C═C--R⁸, --OCH₂ CHR⁷ R⁸, --C.tbd.C--R⁸, --CH═CR⁷ R⁸, --CH₂ CHR⁷ R⁸, --CH₂ C.tbd.C--R⁸, CHR⁷ CH═CHR⁸, and CH═CHCHR⁷ R⁸ ; R³ is selected from H, F, Cl, Br, I; R⁴ is selected from H, F, Cl, Br, I, C₁₋₃ alkyl substituted with 0-3 R¹¹, CH═CH₂, C.tbd.CH, OCH₃, OCF₃, --CN, NO₂, CHO, C(O)CH₃, C(O)CF₃, C(O)NH₂, C(O)NHCH₃, NR⁷ R^(7a), C(O)OR⁷, NR⁷ SO₂ R^(7b), and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; alternatively, R³ and R⁴ together form --OCH₂ O--; and, R⁵ is selected from H, F; R⁶ is selected from H, OH, OCH₃, --CN, F, CF₃, CH₃, and C(O)NH₂ ; R⁷ is selected from H and CH₃ ; R^(7a) is selected from H and CH₃ ; R^(7b) is CH₃ ; R⁸ is selected from H, C₁₋₄ alkyl substituted with 0-3 R¹¹, CH(--OCH₂ CH₂ O--), C₂₋₄ alkenyl, C₃₋₅ cycloalkyl substituted with 0-1 R⁹, phenyl substituted with 0-1 R¹⁰, and 5-6 membered aromatic heterocycle system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 0-1 R¹⁰ ; R⁹ is selected from D, OH, OCH₃, CH₃, and F; R¹⁰ is selected from OH, CH₃, OCH₃, F, Cl, Br, I, CN, NR⁷ R^(7a), and C(O)CH₃ ; R¹¹ is selected from OH, OCH₃, CN, F, Cl, NR⁷ R^(7a), C(O)CH₃, and C(O)NH₂ ; and, p is selected from 1 and
 2. 3. The process according to claim 2, wherein in step (a), the compound of formula II is added to a solution containing the nucleophile.
 4. The process according to claim 3, wherein in step (a), R^(2b) is R⁸ --C.tbd.C--M; and M is selected from Li, Mg, and Zn.
 5. The process according to claim 4, wherein in step (a), R⁸ --C.tbd.C--M is formed in situ by addition of a strong base to a solution containing R⁸ --C.tbd.C--H.
 6. The process according to claim 5, wherein in step (a), the strong base is selected from n-butyl lithium, s-butyl lithium, t-butyl lithium, phenyl lithium, and methyl lithium.
 7. The process according to claim 6, wherein the compound of formula Ia is: ##STR49## the compound of formula Ia is: ##STR50## the nucleophile R^(2b) is lithium cyclopropylacetylide; and, the solvent is THF. 